    [Senate Hearing 116-525]
    [From the U.S. Government Publishing Office]

                                                           S. Hrg. 116-525

                       THE ALZHEIMER'S CRISIS: EXAMINING
                        TESTING AND TREATMENT PIPELINES
                            AND FISCAL IMPLICATIONS

    =======================================================================

                                    HEARING

                                   BEFORE THE

                          SUBCOMMITTEE ON HEALTH CARE

                                     OF THE

                              COMMITTEE ON FINANCE
                              UNITED STATES SENATE

                         ONE HUNDRED SIXTEENTH CONGRESS

                                 SECOND SESSION

                                   __________

                               DECEMBER 16, 2020

                                   __________

    [GRAPHIC NOT AVAILABLE IN TIFF FORMAT]

                Printed for the use of the Committee on Finance

                                  __________

                        U.S. GOVERNMENT PUBLISHING OFFICE
    46-740-- PDF                 WASHINGTON : 2022

    -----------------------------------------------------------------------------------

                              COMMITTEE ON FINANCE

                         CHUCK GRASSLEY, Iowa, Chairman

    MIKE CRAPO, Idaho                    RON WYDEN, Oregon
    PAT ROBERTS, Kansas                  DEBBIE STABENOW, Michigan
    MICHAEL B. ENZI, Wyoming             MARIA CANTWELL, Washington
    JOHN CORNYN, Texas                   ROBERT MENENDEZ, New Jersey
    JOHN THUNE, South Dakota             THOMAS R. CARPER, Delaware
    RICHARD BURR, North Carolina         BENJAMIN L. CARDIN, Maryland
    ROB PORTMAN, Ohio                    SHERROD BROWN, Ohio
    PATRICK J. TOOMEY, Pennsylvania      MICHAEL F. BENNET, Colorado
    TIM SCOTT, South Carolina            ROBERT P. CASEY, Jr., Pennsylvania
    BILL CASSIDY, Louisiana              MARK R. WARNER, Virginia
    JAMES LANKFORD, Oklahoma             SHELDON WHITEHOUSE, Rhode Island
    STEVE DAINES, Montana                MAGGIE HASSAN, New Hampshire
    TODD YOUNG, Indiana                  CATHERINE CORTEZ MASTO, Nevada
    BEN SASSE, Nebraska

                 Kolan Davis, Staff Director and Chief Counsel

                  Joshua Sheinkman, Democratic Staff Director

                                     ______

                          Subcommittee on Health Care

                   PATRICK J. TOOMEY, Pennsylvania, Chairman

    CHUCK GRASSLEY, Iowa                 DEBBIE STABENOW, Michigan
    JOHN THUNE, South Dakota             MARIA CANTWELL, Washington
    RICHARD BURR, North Carolina         ROBERT MENENDEZ, New Jersey
    TIM SCOTT, South Carolina            THOMAS R. CARPER, Delaware
    BILL CASSIDY, Louisiana              BENJAMIN L. CARDIN, Maryland
    JAMES LANKFORD, Oklahoma             SHERROD BROWN, Ohio
    STEVE DAINES, Montana                ROBERT P. CASEY, Jr., Pennsylvania
    TODD YOUNG, Indiana                  MARK R. WARNER, Virginia
    BEN SASSE, Nebraska                  SHELDON WHITEHOUSE, Rhode Island
                                         MAGGIE HASSAN, New Hampshire
                                         CATHERINE CORTEZ MASTO, Nevada

                                      (ii)

                                C O N T E N T S

                                  ----------

                               OPENING STATEMENTS

                                                                       Page
    Toomey, Hon. Patrick J., a U.S. Senator from Pennsylvania,
      chairman, Subcommittee on Health Care, Committee on Finance....     1
    Stabenow, Hon. Debbie, a U.S. Senator from Michigan..............     3

                                   WITNESSES

    Dokholyan, Nikolay, Ph.D., M.S., G. Thomas Passananti professor
      and vice chair for research, Pennsylvania State College of
      Medicine, Hershey, PA..........................................     5
    Bateman, Randall J., M.D., Charles F. and Joanne Knight
      distinguished professor of neurology; and director, Dominantly
      Inherited Alzheimer's Network (DIAN), DIAN Trials Unit (DIAN-
      TU), Washington University School of Medicine, St. Louis, MO...     7
    Mohs, Richard C., Ph.D., chief scientific officer, Global
      Alzheimer's Platform Foundation, Chicago, IL...................     8
    Carrillo, Maria, Ph.D., chief science officer, Alzheimer's
      Association, Chicago, IL.......................................    10

                   ALPHABETICAL LISTING AND APPENDIX MATERIAL

    Bateman, Randall J., M.D.:
        Testimony....................................................     7
        Prepared statement...........................................    35
    Carrillo, Maria, Ph.D.:
        Testimony....................................................    10
        Prepared statement...........................................    36
        Responses to questions from subcommittee members.............    41
    Dokholyan, Nikolay, Ph.D., M.S.:
        Testimony....................................................     5
        Prepared statement...........................................    42
        Responses to questions from subcommittee members.............    48
    Grassley, Hon. Chuck:
        Prepared statement...........................................    49
    Mohs, Richard C., Ph.D.:
        Testimony....................................................     8
        Prepared statement...........................................    50
        Responses to questions from subcommittee members.............    52
    Stabenow, Hon. Debbie:
        Opening statement............................................     3
        Prepared statement...........................................    54
    Toomey, Hon. Patrick J.:
        Opening statement............................................     1

                                 Communications

    Arizona Alzheimer's Consortium...................................    57
    Life Molecular Imaging Inc.......................................    59

                                     (iii)

                       THE ALZHEIMER'S CRISIS: EXAMINING
                        TESTING AND TREATMENT PIPELINES
                            AND FISCAL IMPLICATIONS

                                  ----------

                          WEDNESDAY, DECEMBER 16, 2020

                                   U.S. Senate,
                           Subcommittee on Health Care,
                                          Committee on Finance,
                                                        Washington, DC.
        The WebEx hearing was convened, pursuant to notice, at 2:31
    p.m., Dirksen Senate Office Building, Hon. Patrick J. Toomey
    (chairman of the subcommittee) presiding.
        Present: Senators Grassley, Thune, Portman, Cassidy, Young,
    Stabenow, Cantwell, Menendez, Carper, Brown, Casey, Warner,
    Hassan, and Cortez Masto.
        Also present: Republican staff: Alyssa Palisi, Staff
    Director for Senator Toomey. Democratic staff: Alex Graf,
    Legislative Aide for Senator Stabenow.

      OPENING STATEMENT OF HON. PATRICK J. TOOMEY, A U.S. SENATOR
       FROM PENNSYLVANIA, CHAIRMAN, SUBCOMMITTEE ON HEALTH CARE,
                          COMMITTEE ON FINANCE

        Senator Toomey. Okay; thank you all very much for joining
    us. The attendance at this hearing looks to be terrific, and I
    am very pleased with that fact. I am very grateful to my
    partner on this really, really important topic, Senator
    Stabenow, for all of her dedication to this cause.
        So, welcome to the Senate Finance Subcommittee on Health
    Care hearing ``The Alzheimer's Crisis: Examining Testing and
    Treatment Pipelines and Fiscal Implications.''
        As chair of the subcommittee, it has been a priority of
    mine to highlight the really extraordinary public policy
    challenges that Alzheimer's disease presents. To start with, as
    we all know, Alzheimer's disease is 100-percent fatal. There is
    no therapeutic intervention that can reverse, stop, or even
    slow its progression.
        We do not really understand the mechanism by which it
    carries out its lethal work, but almost 6 million Americans are
    estimated to be living with the disease today--though as our
    witnesses highlight in their testimony, it is very likely that
    that is an understatement. Nevertheless, it is a figure that is
    expected to balloon to nearly 14 million by 2050. Alzheimer's
    is already the sixth leading cause of death for Americans, and
    the morality rate is increasing at an alarming rate.
        Lastly, it is a growing financial burden on our Federal
    health-care programs. According to a study by the National
    Institutes on Aging, the annual cost of dementia in the United
    States is projected to reach between $379 billion and $511
    billion--that is annual--by 2040.
        These problems are compounded by the inequities in the
    Federal funding of Alzheimer's disease, which still does not
    receive its fair share of the NIH investment that is
    commensurate with its out-sized impact on patients, families,
    and Federal health-care programs.
        And further, despite knowing that amyloid plaques and tau
    proteins can begin to quietly develop in a patient's brain
    years before a patient ever experiences symptoms, we still do
    not have a non-invasive, affordable, and rapid diagnostic
    available to the public. The ability to detect the disease
    before neurological decay begins could provide an important
    opportunity for innovative drug makers to develop a treatment
    or a cure.
        On January 4, 2011, the National Alzheimer's Project Act
    was signed into law after being passed unanimously by both
    chambers of Congress. This set forth an ambitious goal to find
    the cure for Alzheimer's disease by 2025. As we enter the last
    5-year stretch toward this deadline, it is time for Congress
    and the public to take a detailed look at the state of
    Alzheimer's disease research, as well as analyze current
    barriers to the potential discovery of effective therapies and
    diagnostics.
        In some ways, this could not be a more timely discussion.
    The race for cures and vaccines for COVID-19 has given
    Americans insight into the capabilities of the pharmaceutical
    and diagnostic industries. When incentives align and public
    policy is made with an eye towards innovation, academic and
    commercial researchers in the United States have proven that
    they are capable of nimbly solving some of our Nation's most
    urgent public health problems.
        Without effective treatments, the social and emotional toll
    of this insidious disease will continue to bear down upon
    patients and their families. With Senator Stabenow's
    partnership, for which I thank her again, this marks our third
    hearing to examine the many difficulties that Alzheimer's
    disease creates for patients, families, and policy-makers.
        In addition, we have sought public input to help inform the
    development of potential future legislation and areas for
    regulatory reform. In October, we recommended 15 regulatory
    actions that the Department of Health and Human Services,
    including the Centers for Medicare and Medicaid Services and
    the National Institutes of Health, can take to improve the
    lives of Alzheimer's patients.
        It is my hope that the incoming administration will swiftly
    pick up where they left off. Unfortunately, legislative work
    does not fix the biggest issue facing Alzheimer's patients and
    their families: the lack of a cure, or even a treatment for the
    disease.
        So today we will hear from key leaders in the field of
    Alzheimer's disease research. We will learn about where
    researchers are in the race for a cure and what more can be
    done to help them get there. I am really looking forward to
    hearing from each of them.
        But before we do that, I will yield to Ranking Member
    Stabenow for the purpose of her opening statement.

              OPENING STATEMENT OF HON. DEBBIE STABENOW,
                      A U.S. SENATOR FROM MICHIGAN

        Senator Stabenow. It is my pleasure to join you in hosting
    this subcommittee hearing, and I know how passionate we both
    are on this issue. And I really appreciate the work that we
    have been doing together on the subcommittee, and appreciate
    all of our colleagues joining us today.
        Also, thank you to our witnesses for all you are doing, and
    for being here virtually today as we discuss this incredibly
    important topic.
        Five-point-eight million Americans are living with
    Alzheimer's today, and that includes 190,000 people in my home
    State of Michigan. In just the next 30 years, that number is
    expected to more than double to 14 million Americans. And we
    know that the pandemic has hit dementia patients especially
    hard, with well over 13,000 excess deaths attributed to
    Alzheimer's since March.
        Behind these numbers, though, are what is most important,
    and that is grandparents, and parents, and aunts and uncles,
    and friends, moms and dads, who have all faced this horrific
    diagnosis and limited treatment actions right now.
        Today, we will learn the latest developments on Alzheimer's
    treatments and testing. There is still no drug, as the chairman
    said, to cure Alzheimer's disease or slow its progression. But
    there is hope.
        I am pleased that the Federal funding for Alzheimer's
    research is five times higher now than it was just 9 years ago,
    and I agree that we need to do much more. With this funding,
    many researchers have been able to make strides toward new
    treatments. I know in my home State, there is tremendous work
    being done.
        We need to continue to support their groundbreaking work,
    and to expand on it. We also need better testing so we can
    identify the disease early and help families plan and get
    people enrolled in clinical trials. And when we have a
    treatment, early and affordable testing and diagnosis will make
    sure that people who need it get it.
        I introduced legislation with Senators Capito, Menendez,
    and 19 others called The CHANGE Act, which will encourage
    timely and accurate detection and diagnosis using evidence-
    based tools.
        Finally, while working toward a cure, we must not forget
    the people who care for their loved ones with the disease. And
    we all know that Alzheimer's really is a family disease. I am
    so glad that the Improving HOPE for Alzheimer's Act was
    implemented on a bipartisan basis, and now newly diagnosed
    Alzheimer's patients can access a doctor's visit to create an
    individual care plan.
        However, not everybody knows of this benefit, and not
    everyone is using it. So our Improving HOPE for Alzheimer's
    Act, co-
    sponsored by 47 members, many on this subcommittee, requires
    HHS to conduct a nationwide campaign to increase awareness of
    this care planning visit and the importance of supporting
    families.
        We also must ensure that once patients and their caregivers
    have a plan, they can actually implement the plan. That is why
    I will be introducing legislation next year--and I welcome my
    colleagues to be a part of this--directing the Department of
    Health and Human Services to test a payment model to support
    coordinated care for dementia patients, as well as support for
    caregivers. By coordinating care, we can reduce complications
    and we can ensure that families have resources to help care for
    their loved ones.
        So I am very proud of the progress we have made in the work
    we are doing together on a bipartisan basis. There is so much
    more to do, and I look forward not only to today's discussion,
    but also for ways that we can continue to work together on
    diagnosis, treatment, and ultimately what we all want, which is
    a cure for Alzheimer's.
        Thank you, Mr. Chairman.
        [The prepared statement of Senator Stabenow appears in the
    appendix.]
        Senator Toomey. Thank you very much, Ranking Member
    Stabenow.
        First of all, without any objection, any other members'
    opening statements will be made part of the record. My
    understanding is a vote is going to be called within the next
    few minutes, and, Senator Stabenow, if I understand correctly,
    you were thinking of maybe voting early, and I will continue
    with the hearing; and when you get back, maybe you could take
    over while I run and vote, if that is okay with you.
        Great. Thank you.
        Well, we have a really remarkable panel today. Their
    contributions to Alzheimer's research and the community of
    researchers has been extraordinary, and I appreciate very much
    each of them taking the time out of their day to join us and to
    educate us on their work.
        First, we will hear from Dr. Nikolay Dokholyan. Dr.
    Dokholyan is a researcher from the Penn State College of
    Medicine. I hope I am pronouncing your name at least
    approximately right, Doctor.
        The mission of his laboratory is to research and develop
    therapeutics that fight against neurodegenerative diseases like
    Alzheimer's. He has been recognized on numerous occasions for
    his contributions to the field of computational biology and
    biophysics.
        Dr. Dokholyan, it is great that you could join us today.
    Thank you for being with us. And let me point out that the
    Commonwealth of Pennsylvania is very proud of your work.
        Next we will hear from Dr. Randall Bateman, a physician
    researcher from the Washington University School of Medicine.
    His laboratory focuses on the causes, diagnosis, and future
    treatments of Alzheimer's disease. Earlier this year, his
    research findings gave the public hope that a rapid and
    inexpensive blood screening test to identify people at high
    risk of developing the disease may be within reach.
        Then we will hear from Dr. Richard Mohs, the chief science
    officer at the Global Alzheimer's Platform Foundation. Dr. Mohs
    has authored or co-authored over 350 scientific papers. Most
    notably, his work describes clinical trials that led to the
    approval of some of the most commonly prescribed treatments for
    Alzheimer's disease today.
        He retired in 2015 after serving in several leadership
    positions at Eli Lilly and spending 23 years with the Mount
    Sinai School of Medicine.
        Last but not least, we will hear from Dr. Maria Carrillo,
    the chief science officer at the Alzheimer's Association. Dr.
    Carrillo oversees the Association's portfolio of research
    initiatives, working with both the national and international
    scientific communities to overcome barriers to research and
    development.
        As a reminder, each witness will have 5 minutes to present
    their oral testimony, which will be followed by questions.
        We will begin with our first witness, Dr. Dokholyan.

        STATEMENT OF NIKOLAY DOKHOLYAN, Ph.D., M.S., G. THOMAS
    PASSANANTI PROFESSOR AND VICE CHAIR FOR RESEARCH, PENNSYLVANIA
                 STATE COLLEGE OF MEDICINE, HERSHEY, PA

        Dr. Dokholyan. Thanks, Senators Toomey and Stabenow, for
    your invitation. I am a scientist whose research is focused on
    fundamental and translational research in neurodegenerative
    diseases at Penn State University College of Medicine.
        I have been studying neurodegenerative disorders for over
    20 years, focusing on fundamental processes that lead to the
    pathological behavior of proteins in human diseases. Besides a
    scientific desire to understand the processes leading to
    neuronal degeneration, it is personal to me. Like many
    Americans, I have family members who have suffered from
    Alzheimer's disease, so I know well the emotional and financial
    toll it takes on families.
        Alzheimer's disease is a progressive, irreversible, and
    degenerative brain disease. Currently, close to 8 million
    Americans are living with this illness, and this number is
    likely a significant under-estimate due to the lack of
    diagnostic tools, early diagnostic tools, and access to health
    care, especially in rural areas, causing many individuals in
    early stages of the disease to remain undiagnosed.
        Age is the most critical factor. And as the U.S. population
    ages, the number of Americans living with Alzheimer's is
    projected to double by 2050. And among the top 10 leading
    causes of death, Alzheimer's is the only one that cannot be
    even slowed.
        The national cost of care for patients is also a staggering
    $300 billion, and that is not including the $240-billion cost
    of unpaid labor from caregivers, families, and friends. And
    these numbers make Alzheimer's disease the most expensive
    disease in the United States. The projected cost of Alzheimer's
    by 2050 will top $1.1 trillion in the United States alone.
        Curative therapeutics targeting disease mechanisms as
    opposed to palliative curative therapeutics to treat symptoms,
    would have the most profound impact on quality of life for
    Alzheimer's patients and their families. And it would eliminate
    the financial burden associated with the disease.
        The principal challenge in identifying curative
    therapeutics is our current dearth of knowledge of early
    molecular events leading to pathological disease processes,
    which can begin up to 20 years before the disease onset, and
    those are poorly understood.
        The principal critical barriers are current technological
    limitations, such as lack of precise and accurate methods for
    noninvasive monitoring of pathological processes in organisms,
    and inadequate experimental animal models of the disease.
        Because of this dearth of knowledge, there is also no
    definitive clinical diagnostic test for Alzheimer's disease. It
    is interesting that circumstantial evidence--such as family
    history, interaction with family members and friends, and a
    battery of cognitive tests--suggests whether the patient
    exhibits signs of dementia. And because the reason for dementia
    is likely Alzheimer's, that is the association given during
    diagnosis. By the time diagnosis is made, though, pathology has
    altered, significantly and irreversibly, the brain.
        One of the hallmarks of Alzheimer's disease is the
    accumulation of barren protein deposits in a patient's brain.
    However, despite decades of research, we have not yet
    established the nature of the link between aggregation and
    toxicity, nor whether protein aggregates are indeed a driver of
    neuronal death or simply a consequence of some unknown
    processes.
        Nevertheless, the protein aggregation has been the basis
    for many Alzheimer's disease drugs in the drug pipeline--which
    have been expensive failures. The for-profit private sector is
    driven by deliverables, and thus, despite remarkable spending
    on R&D, companies typically focus on only the established
    target drug therapies, which reflect our fundamental
    understanding of disease pathological processes, an
    understanding that is typically established in academia,
    because it takes a long time.
        Hence, deeper integration of the private sector with
    academia may significantly reduce the inertia in the drug
    pipeline and increase the potential for new ideas to tackle
    neurodegeneration.
        Translational science programs aimed at marrying these
    scientific fields with clinical research are critical to
    establishing a working model of the disease. The success of
    translational science relies on attracting scientists with
    backgrounds in diverse fields to build interdisciplinary
    programs. In addition, attracting industrial partners to these
    interdisciplinary consortiums will facilitate their progress.
        Finally, I want to mention that there is an additional way
    we can help with Alzheimer's, because the dominant cost
    associated with caring for Alzheimer's patients stems from the
    expensive care requirements in later stages of the disease.
    Thus, reducing the cost of care is mostly an untapped direction
    in mitigating the financial burden of the illness.
        Recent scientific and engineering innovations, especially
    in machine learning and artificial intelligence, wireless
    solutions, and miniature devices, may offer new and
    unparalleled means for caring for patients, especially in
    advanced stages of the disease.
        Facilitating innovations through Federal and private-sector
    programs will have a major impact on improving the quality of
    care and reduce the financial burden on both government
    programs and individuals.
        Thank you, Senators, for your attention.
        [The prepared statement of Dr. Dokholyan appears in the
    appendix.]
        [Pause.]
        Senator Toomey. Dr. Bateman, can you hear me?
        Dr. Bateman. Yes.
        Senator Toomey. All right, you are recognized for 5
    minutes.

     STATEMENT OF RANDALL J. BATEMAN, M.D., CHARLES F. AND JOANNE
      KNIGHT DISTINGUISHED PROFESSOR OF NEUROLOGY; AND DIRECTOR,
     DOMINANTLY INHERITED ALZHEIMER'S NETWORK (DIAN), DIAN TRIALS
     UNIT (DIAN-TU), WASHINGTON UNIVERSITY SCHOOL OF MEDICINE, ST.
                               LOUIS, MO

        Dr. Bateman. Chairman Toomey, Ranking Member Stabenow, and
    members of the committee, I would like to thank you for the
    opportunity to speak today on the important topic of
    Alzheimer's disease and advances in medical diagnosis and
    treatment.
        In the research field, we have come a long way in our
    understanding of the disease; our ability to detect, track, and
    diagnose Alzheimer's; in research and in the clinic now; and in
    development of drugs which can stop and reverse some
    Alzheimer's disease pathologies.
        We have specific tests that can identify the two key
    pathologies of Alzheimer's--amyloid plaques and tau tangles--in
    brain scans, cerebral spinal fluid, and now in the blood.
        Treatments targeting amyloid plaques can remove these
    plaques to undetectable levels, something that was not possible
    just a few years ago. We are learning from clinical trials how
    to dose these medications more effectively and who is likely to
    benefit from them.
        However, there are clear opportunities to accelerate the
    developments in the diagnostic, therapeutic, and research
    pipelines for Alzheimer's disease. New Federal strategies could
    enable breakthroughs in the disease's diagnosis and treatment
    similar to what has been accomplished for diagnostics and
    vaccines for the COVID-19 pandemic.
        The two areas that represent challenges to therapeutic
    development are centered on issues of regulatory burden and
    risk-averse trial designs. And sometimes lack of urgency and
    not accounting for the cost of inaction leads to clinical trial
    delays and higher overall costs.
        Extensive international regulatory reporting requirements
    and approval delays cause major trials to cost several hundred
    million dollars and take 3 to 5 years to complete, while
    prevention trials take even longer at about 7 years. These
    trials are too expensive and too long, causing potential
    treatments to be left on the shelf untested and some drug
    developers to abandon Alzheimer's drug development programs.
        If we can learn from COVID-19 approaches in how to
    accelerate and implement better strategies to move more
    quickly, and appropriate incentives can be made, an accelerated
    development can occur to lead to faster treatment development.
        How can this be helped? One way is that policy-makers and
    agencies can enable and support standards which account for the
    personal and the financial cost of Alzheimer's disease in terms
    of the opportunity costs of delays in decision-making. In other
    words, balance the risk/benefit analysis to account for time
    lost on deliberations.
        Two, enable science and medicine to advance at optimal
    speeds, accounting for potential benefit while managing risk.
    This has largely been started with very significant support to
    the NIH through the Senate and the government, and this is
    already paying out in dividends.
        Number three, encourage investment in the development of
    treatments and preventions for Alzheimer's disease.
        As a second discussion point on diagnostics, I believe that
    we are currently in a very good position in terms of having
    highly accurate diagnostic measures of Alzheimer's disease for
    amyloid plaques and tau tangles, the two pathologies which
    define the disease. These have been available for a number of
    years, and more recently simple blood tests have been developed
    that can also detect these pathologies. But they are not used
    in the clinic yet, for several reasons, including lack of payer
    support.
        Symptomatic patients and their doctors have a need to know
    an accurate diagnosis. These tests can accurately identify who
    has Alzheimer's disease pathology and, importantly, who does
    not have Alzheimer's disease, so that other causes can be
    sought, including treatable or reversible causes.
        For research purposes, measurable indicators of Alzheimer's
    disease pathology, what we call ``biomarkers''--such as blood
    and cerebral spinal fluid, amyloid, and tau--offer immense
    promise. These biomarkers are being used to screen for the
    disease, track the effects of treatment on Alzheimer's disease
    processes, and are also being considered for surrogate
    biomarker development, which would greatly speed Alzheimer's
    disease trials.
        Thank you.
        [The prepared statement of Dr. Bateman appears in the
    appendix]
        Senator Toomey. Thank you, Dr. Bateman.
        Dr. Mohs, you are recognized.

    STATEMENT OF RICHARD C. MOHS, Ph.D., CHIEF SCIENTIFIC OFFICER,
          GLOBAL ALZHEIMER'S PLATFORM FOUNDATION, CHICAGO, IL

        Dr. Mohs. Thank you, Senators Toomey and Stabenow, and
    members of the subcommittee, for your support for Alzheimer's
    research and for the opportunity to testify.
        For the past 40 years, both as an academic researcher
    funded by the National Institutes of Health, and subsequently
    leading drug development teams in the pharmaceutical industry,
    I have devoted much of my scientific career to trying to
    develop new medicines for Alzheimer's disease.
        We have not been as successful as I would like, or as
    successful as patients need. Currently, I am the chief science
    officer for the Global Alzheimer's Platform, or the GAP
    Foundation. It is a
    patient-centered nonprofit organization devoted to accelerating
    the delivery of innovative therapies for AD by reducing the
    duration and cost of clinical trials.
        More than 85 centers across the U.S. and Canada are part of
    the growing GAP network. These research sites are supported by
    GAP by assisting with study startups, with the recruitment
    activities, promoting diversity in research studies, and
    offering national programs that champion brain health and the
    citizen scientists who make research possible.
        Based on my experience, I can offer some perspectives on
    barriers to progress and future initiatives that could speed
    progress that is urgently needed. I think you will find some of
    my recommendations mesh quite well with the remarks of the
    first two speakers.
        The first and most significant barrier to progress is that
    we have not yet clearly identified the key biological processes
    that cause AD. As we have learned in recent months from the
    experience of COVID-19, once a causal agent is identified and
    characterized biologically, the search for preventative
    measures and treatments can proceed rationally through highly
    informative basic and clinical research.
        For a chronic disease such as Alzheimer's with multiple
    risk factors and complex pathology, the path to effective
    treatments is very uncertain. In the private sector, there is a
    high degree of interest, and there has been considerable
    investment in Alzheimer's drug development, but it is
    considered more risky than other areas where the perceived
    likelihood of clinical and commercial success is higher.
        We do know that AD is characterized by the presence of two
    abnormal proteins in the brain, amyloid and tau. Many drugs
    designed to slow the accumulation or speed the removal of
    amyloid or tau have been entered into large, time-consuming,
    and very expensive clinical trials.
        While these approaches may show some efficacy in some
    patients, it is an imperative that the therapeutic value of
    targeting other factors associated with AD pathology be tested
    as quickly as possible.
        Given the complexity of AD, we must expect that many
    clinical trials, even those testing the most scientifically
    promising drug candidates, will fail to show efficacy. By
    testing a variety of scientifically justified approaches, an
    efficient and well-executed clinical study, and learning from
    each set of studies, I am very confident that we will
    eventually develop effective medicines for the prevention and
    treatment of AD.
        A second major barrier, following on Dr. Bateman's
    comments, is the disconnect that now exists between the way
    patients with AD are diagnosed in clinical practice and the way
    research studies identify participants. Most practicing
    physicians make a diagnosis of AD relatively late, when
    patients manifest clear symptoms and need counseling on how to
    manage those symptoms.
        Recently, major advances have been made in the development
    of brain scans and blood-based biomarkers that will speed the
    early identification of patients with asymptomatic disease,
    both for trials and for early diagnosis in clinical practice.
        Early diagnosis will allow for scaling up education efforts
    and counseling so that families can make plans for their loved
    one to have the highest degree of independence possible. Early
    diagnosis will also facilitate the rapid completion of clinical
    studies because we will identify and enroll appropriate
    participants in clinical trials much earlier and much faster.
        The GAP Foundation is in the process of standing up a
    platform study that will test the efficacy of more than a dozen
    promising blood biomarkers and digital cognitive assessments
    for AD. Known as the Bio-Hermes study, we will generate
    biological samples for over 1,000 participants. The Bio-Hermes
    study will include racially and ethnically diverse participants
    in order to assess whether biomarker risk factors vary by race
    and ethnicity.
        Recruiting a diverse group of participants for Alzheimer's
    clinical trials is both extremely important and challenging. To
    help address this issue, GAP has committed to recruiting at
    least 20 percent African American or Latino volunteers for the
    upcoming Bio-Hermes study.
        Our intention and hope is that the Bio-Hermes study will be
    a model for building back a clinical trial infrastructure that
    is more efficient and gets to better diagnostics and treatments
    faster.
        The FDA, of course, is an essential partner when it comes
    to research for better diagnostics and treatments. We applaud
    the agency's approach to public engagement around their
    evaluations. Given the need for greater diversity in clinical
    trials, we hope Congress will use the Prescription Drug User
    Fee Act renewal process to encourage FDA to develop clear
    guidance on minimum standards for diversity.
        Undoubtedly, Alzheimer's disease has proved to be one of
    the most difficult problems ever to confront biomedical
    researchers. I look forward to discussing how the subcommittee
    can take steps to speed the widespread use of blood and digital
    biomarkers; increase the speed and diversity of Alzheimer's
    clinical trials; enhance investment in the AD clinical research
    infrastructure and the clinical trial pipeline; and encourage
    further collaboration between commercial sponsors, academic
    researchers, NIH, FDA, patients, and CMS.
        Thank you very much.
        [The prepared statement of Dr. Mohs appears in the
    appendix.]
        Senator Toomey. Thank you, Dr. Mohs.
        Dr. Carrillo, you are now recognized.

      STATEMENT OF MARIA CARRILLO, Ph.D., CHIEF SCIENCE OFFICER,
                  ALZHEIMER'S ASSOCIATION, CHICAGO, IL

        Dr. Carrillo. Thank you, Chairman Toomey, Ranking Member
    Stabenow, and members of the subcommittee. I really appreciate
    you holding this important hearing today and the opportunity to
    testify on Alzheimer's and other dementia therapeutic and
    diagnostic pipelines, as well as of course Federal policies
    that can help address barriers to foster much-needed
    breakthroughs in diagnosis and treatment.
        I have been personally touched by dementia, as I know many
    of you have. My mother-in-law Arcelia Pachicano, my father-in-
    law Jose Pachicano, passed away over 3 years ago, within 1 year
    of each other, Arcelia of Alzheimer's dementia and Jose of
    vascular dementia. Arcelia in fact was the third of four
    siblings to die of Alzheimer's, and her father died of it also.
        Our family is committed to doing everything we can to
    eradicate this disease that affects so many, including the next
    generation.
        In addition to the suffering caused by this disease to
    families like my own, like many of yours, Alzheimer's is an
    enormous drain on the health-care system and on our Federal and
    State budgets. And while there are, as we have already heard,
    over 5 million Americans living with the disease today, without
    significant action, nearly 14 million Americans will have it by
    2050.
        And as you heard also earlier in this hearing, in 2020,
    Alzheimer's and other dementia alone will cost our Nation $305
    billion, including $206 billion for Medicare and Medicaid.
    Unless we find a way to stop this, by 2050 Alzheimer's is
    projected to cost more than $1.1 trillion. But there is hope on
    the horizon.
        We have great promise with historic funding increases
    coming from Congress that have made Alzheimer's and related
    dementia research more of a priority at the NIH. In fact, since
    Congress passed the bipartisan Alzheimer's Project Act 10 years
    ago, Alzheimer's NIH research funding has increased more than
    sixfold. This investment has been critical to progress towards
    our primary research goal to effectively treat and prevent
    Alzheimer's by 2025, including advances in new biomarkers to
    detect the disease.
        You have also heard that biomarkers are the most promising
    paths because they can detect the earliest brain changes. The
    FDA has already approved PET scans to identify the hallmarks of
    Alzheimer's--amyloid plaques and tau tangles in the brain--and
    they are currently reviewing an application for cerebrospinal
    fluid as well. We are closer to a blood test, which you have
    also heard, and this breakthrough is critically important and
    actually was very well-represented for the first time at the
    Alzheimer's Association's International Conference this past
    July, showing that these blood tests might even be able to
    detect changes 20 years before Alzheimer's symptoms occur.
    Biomarkers will be the new diagnostic tools in the toolbox for
    primary care physicians and specialists in the early detection
    and most accurate diagnosis of Alzheimer's.
        And in addition to these great advances, there is a drug
    under review right now at the FDA that for the first time may
    very well treat the underlying biology of the disease--a very
    important moment for the Alzheimer's field.
        With more shots on goal than ever before, there is
    excitement in the research community and hope for the millions
    of Americans and families devastated by this disease. But even
    with these great strides, there is a lot left to be done. We
    all know that, and have heard this already from other witnesses
    here at the hearing.
        We need to understand the changes, the underlying changes
    that really are underlying the disease progression. This is in
    large part, I think, important because we also do not know how
    to differentiate that impact, that underlying biology, in terms
    of the types of individuals to actually recruit for our
    clinical trials. So we have an extraordinary under-
    representation of black African Americans, Hispanic Latin
    Americans, Asian Americans, and Native Americans, which should
    be representative of the United States population.
        This under-representation not only hinders the ability of
    researchers to understand health disparities but also restricts
    our knowledge on how approved therapies or diagnostics may be
    generalized to the whole population, and to those actually who
    may need the drug most.
        It is crucial that we continue to increase our investment
    in order to maximize every opportunity for success. This will
    enable us to learn more ways in which Alzheimer's develops in
    the brain in everyone, develop better diagnostics, and discover
    more effective treatments.
        The Alzheimer's Association and AIM urge Congress to
    finalize the additional $354 million for NIH Alzheimer's
    funding for fiscal year 2021, which was included in the recent
    Senate draft. We cannot afford to leave any stone unturned.
    With every study, we are illuminating more of the underlying
    biology of Alzheimer's and finding another piece in the puzzle.
        Despite more than 2 decades of advances in this disease,
    Alzheimer's and other dementia are often unrecognized, or even
    misattributed in physicians' offices. This causes delays that
    you have already heard could be harmful to an individual, and
    even costly.
        There clearly is no consensus for Alzheimer's diagnostic
    recommendations in primary care. That is why the Alzheimer's
    Association developed, along with a group of physicians, 20
    recommendations for practitioners across the country. Thus, the
    Alzheimer's Association looks forward to working with all of
    you, and with physician groups, to ensure that primary care
    doctors and dementia experts, and even nurse practitioners, can
    adopt new guidelines.
        With all of the recent progress in research in Alzheimer's,
    and biomarkers specifically, we need to make sure that there is
    actually coverage for these diagnostic tests. Coverage for
    diagnostics would spur our private sector in engagement on both
    diagnostics and therapeutics, actually--diagnostic testing with
    validated biomarkers crucial for Alzheimer's, which you have
    already heard as well. And the Alzheimer's Association has
    worked very well with the Centers for Medicare and Medicaid
    Innovation since 2013 to explore this coverage through the
    IDEAs Study.
        As a co-chair of the IDEAs Study, we are seeking evidence
    to support that reimbursement that is very important, by
    Medicare of course, and third-party payers. But also we are
    building on the IDEAs Study in order to launch the New IDEAs
    Study which will actually specifically look for the impact of
    amyloid PET scans on diagnosis in more diverse, historically
    under-represented populations.
        And one theory of course that you have already heard about
    is increasing the availability of therapeutics in the under-
    diagnosed populations because, as you have already heard, when
    the diagnoses are made, it may be very well too late.
        So we must continue to work on early detection in order to
    provide dementia care for those who need it the most.
        So thank you very much for the opportunity, Senators
    Stabenow and Menendez, and of course for introducing the
    bipartisan Improving HOPE for Alzheimer's Act, and we look
    forward to working with you on everything we can do in order to
    accelerate progress.
        Thank you, very much.
        [The prepared statement of Dr. Carrillo appears in the
    appendix.]
        Senator Toomey. Thank you very much, Dr. Carrillo.
        I am sorry to put Senator Carper on the spot here, but I
    have not had a chance to vote yet. We have run out of--time has
    expired, so I am wondering, Senator Carper, if I could impose
    on you to lead off with questions, and perhaps to recognize the
    next Senator, until I am able to vote and get back to this
    hearing.
        Senator Carper. Pat, I have not voted.
        Senator Toomey. Okay.
        Senator Carper. But I am happy to take the hand-off. And as
    soon as I am running out of time, I will--if nobody is here, I
    will just go to recess, and we will reconvene as soon as you
    get back, or----
        Senator Toomey. Okay. All right; thank you very much. I
    will run right now and be back as soon as I can.
        Senator Carper [presiding]. Sure. Thank you
        Let me just ask of our witnesses--first of all, I am Tom
    Carper from Delaware. I see Senator Cortez Masto. Catherine,
    have you already voted? Okay. A couple of questions, if I
    could--or, Catherine, do you want to go first?
        Senator Cortez Masto. If you like, Tom, I am happy to. I
    will be very quick. I will not use all of my 5 minutes.
        Senator Carper. Okay, go ahead. Go ahead.
        Senator Cortez Masto. I know we all have to vote. Thank
    you. I appreciate that.
        So I would say, thank you for all of the good work. I am
    similar to many of you, in my family with Alzheimer's, and my
    grandmother died from Alzheimer's. So it has been something
    that has been so important for me. That is why--I was
    fortunate, when I first got to the Senate, to partner with
    Senator Susan Collins to pass the BOLD Infrastructure for
    Alzheimer's Act.
        And so, let me start there. In 2018 we passed that act, and
    the bill aims to activate a full-fledged public health response
    to Alzheimer's disease by building up education opportunities
    through centers of excellence, expanding local and State public
    health infrastructure across the country, through cooperative
    agreements with the CDC, and by offering dated grants to
    improve analysis and timely reporting of data on the disease.
        Now I am fortunate, also, in the State of Nevada to have
    the Lou Ruvo Center for Brain Health in Las Vegas. But let me
    ask this question, and maybe, Dr. Dokholyan, let me start with
    you. Can you speak to the work or research that you would like
    Federal partners to be engaged in that would support the public
    health approach to treating Alzheimer's? I am curious about
    your thoughts on that.
        Dr. Dokholyan. Thank you for--this is a very interesting
    question. So there are several--there is, unfortunately, not
    one single-scope solution. But there are things that the
    government and industry can work together on towards potential
    solutions.
        The first one: I feel like there should be a better
    integration for the research that is done by medical companies
    with academic research. Most of the fundamental research is
    done in academia, and it is very expensive. And so by
    outsourcing all of the research--not all, but the majority of
    the fundamental research--to academia, the companies can save
    money on those processes and focus more on bringing the drugs
    to the market.
        So, supporting those kinds of programs through centers that
    would combine expertise from both academia and industry would
    naturally help, and governmental incentives may be a good way
    to go.
        And companies like Merck and GSK, for example, already have
    programs in place like this. And I think it's one good way to
    go.
        The second I would like to mention is that we focus on
    finding drug targets, true drug targets that would really
    eradicate the disease. It is still in process, and as a
    scientist, nobody can really--I cannot give a timeline when
    this will be discovered. But meanwhile, we have a huge burden
    associated with care management. And care management is a huge-
    ticket item, both to the government and also to family members.
    And developing new technologies that would help monitoring
    Alzheimer's patients--helping them not to wander outside of the
    range and get lost and get frozen to death, for example, as I
    heard from some doctors happens to patients.
        This can be really stopped with simple solutions,
    innovative solutions that would use tracking devices and
    geotracing tools. So there are many ways we can combine
    approaches to help both reduce the suffering of the patients
    and the families, as well as the financial burden.
        Senator Cortez Masto. Thank you, Doctor. Thank you so much.
        I am going to go vote. I will try to get back for the rest
    of the conversation, but, Tom, I will give it back to you.
        Thank you so much.
        Senator Carper. Tell them I am on my way, okay?
        Senator Cortez Masto. I will
        Senator Carper. I will be right behind you.
        Folks, we have a series of two votes. So this is the first
    of two votes. So we have to run and vote, and we will vote
    immediately on a second one, and then we will be back to rejoin
    you. So please be patient, and we will see you shortly. Thank
    you so much. This is of great importance to all of us, and
    personally as well. Thank you.
        [Pause.]
        Senator Toomey. I would like to resume the hearing, and my
    colleagues will be returning as they have a chance to cast
    their votes.
        So let me recognize myself for some questions. And let me
    start with an observation. I alluded to this in my opening
    comment. The Federal Government years ago established the goal
    of having an effective treatment for Alzheimer's by 2025.
        Each of your testimonies brought attention to issues that
    underscore what I think we already know, which is that it looks
    unlikely that we are going to reach that goal, at least on the
    path that we are on now, especially since, as best that I can
    tell, we still do not really understand the dynamics that cause
    this disease, which would presumably be an important
    precondition for having an effective cure.
        But let me put it to you and get your take on this. In your
    professional opinions--and I would like to address this to each
    of our witnesses, and maybe you could just answer in the order
    in which you gave your testimony--do you think we are on track
    to reach the goal of having a cure, or at least an effective
    treatment, by 2025?
        Dr. Dokholyan. The ability to develop, to design therapies
    for complex diseases such as Alzheimer's depends on our
    understanding of the target. So there may--it is very hard to
    make predictions of what the science will bring in the next few
    months. It may be there will be a big breakthrough that will
    say ``here is the problem.''
        But unfortunately, it is hard to predict. And
    unfortunately, there is also inertia regarding what kind of
    ideas we have about the disease. We still do not know whether
    the protein clumps that we believed before were toxic may not
    have anything to do with the toxicity, and are just some
    bystanders there. And so it creates a huge problem for us in
    order to even think about new ways to treat the disease.
        Dr. Bateman. To answer the question, I do not think it is--
    excuse me. Should I speak?
        Senator Toomey. Dr. Bateman, yes.
        Dr. Bateman. Okay; thank you. To answer the question, I do
    not think it is likely that we will have a cure by 2025, or a
    highly effective treatment, at the current rate that we are
    moving. And effective--it needs to be qualified with what we
    mean by ``effective.'' But clinically, what I mean by that is
    things that patients would recognize as stopping or preventing
    the disease, or slowing it to such a degree that it would be
    clinically recognizable by the patient and the family.
        And as I tried to detail, I think one of the issues here is
    that Alzheimer's disease is a very challenging disease to do
    clinical trials on and to demonstrate therapeutic efficacy in.
    These trials are long. The disease progresses slowly. As has
    been highlighted, there are uncertainties as to what is causing
    the immediate damage.
        That is not to say that we do not know of examples. For
    example, there are people for whom we know exactly what is
    causing Alzheimer's disease due to genetic mutations that alter
    these amyloid beta proteins. And on those individuals we have a
    strong understanding of what causes the disease. But it is not
    like an infectious disease where we can point to an infectious
    agent like a virus and say that is the sole cause of the
    disease.
        That said, I do think there are ways to accelerate this
    over the next 4 years to move our chances of coming across and
    identifying and implementing these strategies. And I think one
    strategy is to try to accelerate the way that we do clinical
    trials--launch, implement, and run them.
        Dr. Mohs had reviewed some of the strategies being
    developed to try to do that.
        Two, is to try to treat the disease in a prevention mode.
    So intervening in the disease process before organ and brain
    damage is done, and that I think has, biologically and
    medically, perhaps one of the better shots of being able to
    have a large impact into this medical disease that afflicts so
    many.
        Senator Toomey. Dr. Mohs?
        Dr. Mohs. Yes, thank you, Senator.
        Here is my perspective on this. I think failure to show
    efficacy is probably the norm in drug development. Anybody who
    has worked on developing drugs in any therapeutic area spends
    most of their time working on things that do not turn out to be
    efficacious.
        The problem is even much greater in Alzheimer's disease
    where, if you looked across the industry and academia, the
    failure rate for new compounds being tested is much higher for
    Alzheimer's disease than it is for, say oncology or diabetes or
    heart disease--not that they do not have failures as well. But
    what that tells me is that, to increase the likelihood of
    eventual success, we need to enter lots of different things
    into clinical testing.
        There are ideas out there about other ways to approach this
    disease besides amyloid and tau, and we need to explore as many
    of them as possible.
        So I guess my final answer to you about 2025 is, I think it
    is currently unlikely. My confidence that we would meet that
    goal would be a lot greater if I thought that there were a lot
    more things being tested in effective trials.
        Senator Toomey. Thanks, Dr. Mohs. Dr. Carrillo?
        Dr. Carrillo. Thank you very much, Chairman Toomey. I am
    going to be a little bit more hopeful than my colleagues. I
    think that it is a very hopeful time for Alzheimer's and other
    dementia research. At this moment, for example, we have at
    least one drug that is very different from the others that we
    have approved today, sitting at the FDA for consideration.
        I do think we have more shots on goal today than we did
    before in phase 2 and 3 of the FDA's rigorous process. And what
    happens with those drugs is really what is going to determine
    whether we will meet the 2025 goal.
        I agree with others that investments now in biomarkers to
    help us identify the hallmarks of other brain changes are
    critical. And of course we can leave no stone unturned, and we
    ourselves with our Part the Cloud program are funding 65
    trials, most of which are not in amyloid and tau, to look for
    these other approaches.
        All of that is going to help us get to the end. Whether we
    make it by 2025 is really going to be determined by what is
    right now maturing in the phase 2 and phase 3 pipeline.
        Thank you.
        Senator Toomey. Thank you very much.
        I want to go to Senator Stabenow now. Senator Stabenow, can
    you hear me?
        Senator Stabenow. I can, Mr. Chairman. I apologize as I,
    after I voted, moved to a different office to resume the
    meeting. The wonderful technology is not allowing me to get in
    on video. But I am very appreciative of all of our witnesses
    and the important testimony, and the questions that you and
    colleagues have been asking.
        So I would start with Dr. Bateman. You discussed the
    barriers to developing diagnostic tests in your testimony. And
    as I mentioned in my opening statement, I have introduced the
    CHANGE Act with several of our colleagues that would support,
    as you know, timely detection and diagnosis through using
    cognitive impairment tools during the Medicare annual wellness
    visit.
        I wonder if you might discuss more how critical it is to
    diagnose the disease early, of course accurately, and
    additionally, could diagnostic tests be used to screen patients
    for Alzheimer's disease? And how can we support the research to
    really focus on that early detection, and potentially
    prevention at some point?
        Dr. Bateman. I think this all goes together. And I like to
    point to several other areas in medicine where there is clear
    success in terms of ability to muster resources and attack very
    difficult problems in substantial ways.
        And so, for example in oncology and cancer trials,
    currently there are more than 12,000 active cancer trials.
    There are 348 actively enrolling Alzheimer's disease trials
    today. Why is that so different?
        There are many reasons why that is different, but one of
    them is what you alluded to. And one issue is being able to
    identify the people for trials and having these people enrolled
    and involved in the disease process.
        So for example, there are National Cancer Institute Centers
    where the majority of patients who are seen are diagnosed and
    referred to research clinical trials. And in Alzheimer's, we
    have the opposite problem. Most people who are diagnosed, of
    those who are diagnosed, are not referred to clinical trials or
    research trials.
        And it is part and parcel of a bigger issue where the
    identification and the diagnosis are a challenge in the clinic,
    and it has been a very difficult challenge in research. Through
    technological advances, this is getting better because now, in
    addition to PET scans and spinal taps and cerebral spinal fluid
    tests, we have blood tests that have been developed and are
    being developed to implement.
        So this will improve our ability to outreach to people in
    rural areas, a broader socioeconomic status class, across other
    populations, and engage more of the population in research and
    in trials.
        In terms of what can be done, in the clinic when you see
    patients and families, oftentimes a specialty clinic like ours
    will interview and review with a patient and the family the
    symptoms they all see at the time. We will order a set of tests
    to look for further causes of the disease. We will do the
    cognitive testing you described, which is very important to
    assess the current stage of that person's cognitive
    performance.
        But to date we have not really had available the ability to
    implement specific diagnostic tests of Alzheimer's disease. And
    if that can be accomplished, if we can bring into the clinic
    the ability to have specific tests of Alzheimer's pathology,
    this will change the way in which we manage patients; first, in
    the diagnosis of how we decide who has Alzheimer's and who does
    not, and then next, what we do in terms of treatment and
    management for these individuals.
        And I think it is very reasonable that once people really
    get tested and understand with an objective test this either is
    or is not Alzheimer's, that will change the interest and the
    capacity to do many more trials.
        As I tried to emphasize in my testimony, I do think the
    number of trials, the number of shots on goal, the number of
    attempts that we can make against this disease, is a direct
    function of how quickly we will achieve finding and
    implementing a highly effective treatment.
        Senator Stabenow. Thank you. I know my time is running out
    here, but I have many questions we will follow up on. But, Dr.
    Carrillo, I wanted to ask, particularly as we are looking to an
    alternative payment model in what we want to work on next year,
    in your written testimony you discussed the importance of
    properly managing Alzheimer's and other dementias as a way to
    improve the quality of care and quality of life for people, and
    we know that Alzheimer's is one of the costliest conditions
    facing seniors and families as well as, frankly, Medicare and
    our care system.
        How will managing Alzheimer's and other dementias impact
    the cost of the disease?
        Dr. Carrillo. Thank you very much, Senator Stabenow, for
    that question. Health-care utilization is significantly higher
    among seniors with dementia than among seniors without. And
    that is an important fact that we all know.
        The annual hospitalization rate is twice as high, and the
    use of skilled nursing facilities is nearly four times higher.
    And both hospital and skilled nursing facility stays are nearly
    four times longer.
        Additionally, on average a senior living with dementia will
    visit the emergency room more than once a year. All that adds
    up. And I think one example, a clear example of the
    differentiation is, someone with diabetes and Alzheimer's costs
    Medicare 81 percent more each year than a senior who has
    diabetes alone without Alzheimer's.
        So the total average per person for Medicare spending on
    seniors with Alzheimer's and other dementias is more than three
    times higher than seniors without Alzheimer's. Many of these
    costs are simply unnecessary and could be avoided if care was
    properly managed. Proper care for those diagnosed with dementia
    includes better coordination of the care, seamless navigation
    across the multitude of providers that older individuals have
    to see, and of course, finally, access to care and
    intervention.
        This comprehensive coordination should be reimbursed
    accordingly. And ensuring that clinicians have the resources
    they need to deliver all of that is going to be critical to
    answering your question.
        Senator Stabenow. Well, thank you. And, Mr. Chairman, I
    think that is such an important point, and not only about
    quality of care, but addressing costs in a better way as well.
        So thank you very much, and thanks again to all of our
    witnesses today.
        Senator Toomey. Thank you, Senator Stabenow.
        I am going to ask another question, and I think we have
    several of my colleagues who are voting now and will be
    returning, so let me proceed while we await their return.
        And maybe Dr. Dokholyan could take the first shot at this
    one. And my question is, within the community of researchers, I
    imagine there is a wide range of opinions and ideas, but are
    you aware of whether much research has been done on the
    possibility that the initial cause of Alzheimer's is some kind
    of pathogen?
        Dr. Dokholyan. Certainly that is a really great question.
    Certainly there is a lot of discussion of a sort of infectious
    origin. However, there is really no definitive answer yet to
    that.
        The problem, I feel, is more--the problem is more diverse
    in the sense that it is multi-scale. The problem is multi-
    scale, because the physiology and manifestation that we see in
    patients happens when some proteins misbehave at a tiny little
    scale, on a nanometer scale.
        And so, connecting the scales is creating a huge problem of
    generating ideas of what happens at each scale and connecting
    the scales between them. For example, the principal challenge
    in understanding pathophysiology to me is creating a cell-
    consistent model of disease across the scales from molecules to
    cells to organs. And in many cases, our models at the molecular
    level do not translate to what happens at the cellular level.
        A good example of it is data that the peptide does not
    actually like aggregating at the molecular level and
    physiological concentration. But for some reason, in the
    cellular milieu, it forms clumps. So there is a lot of
    disconnect between scales. And while we can guess that there
    may be some triggers--so there are triggers potentially--that
    are of foreign origin, it does not really rule out the triggers
    within us.
        And so at this point, I feel like it is too early to tell.
    That is my take on it. Thank you.
        Senator Toomey. And is there research that is underway to
    try to shed more light on this question?
        Dr. Dokholyan. There were several papers that were
    published last year in Nature, a very prestigious scientific
    journal, stating that there is an infectious origin that
    triggers production, over-
    production of amyloid beta in the brain, as sort of a defense
    mechanism. And that trigger produces the pathological effect.
        However, it is not--I do not think it is well-established
    knowledge yet, and I am sure people are working on it at this
    moment.
        Senator Toomey. Thank you very much.
        Dr. Mohs, maybe you want to take this question. My
    perspective as a layman is that a number of leading
    pharmaceutical companies, after years and many billions of
    dollars of research, seem to have pulled back from some of the
    research, especially with respect to early-stage disease drugs.
    And I wonder, first of all, if that is an accurate perception,
    if you think that is in fact what is happening? And if so, what
    can and should be done to increase drug manufacturer engagement
    in the early stages of this disease?
        Dr. Mohs. Yes, thanks. I think your perception is partly
    true, but it is not completely true. It is a fact that several
    companies spent very, very large amounts of money moving
    molecules which looked scientifically very interesting into
    these large late-phase phase 3 trials that cost hundreds of
    millions of dollars. And, for the most part, those compounds
    did not show efficacy.
        So I think there has been, not a leaving of the field, but
    I would say a retrenchment a bit, where pharmaceutical
    companies large and small are looking more broadly at different
    approaches to amyloid and tau, but also other potential
    approaches to the disease. And they are searching for ways to
    resolve some of the scientific uncertainty about these
    approaches with smaller studies, rather than always going to
    these very large, late-phase trials.
        So there has been a shift, in my view, in a lot of the
    activity from late-phase trials, high-profile and very
    expensive, to lots of looking at earlier-stage molecules,
    smaller trials, trying to understand whether or not any of
    these new approaches might be valuable. And in many cases,
    these smaller trials are being undertaken either exclusively or
    in partnership with smaller biotechnology companies.
        One of the problems some of those companies face, though,
    is that they may have more difficulty in securing funding.
        So that is the way the field has changed, I think. I would
    like to see efforts taken to make sure that that pipeline of
    early-stage compounds remains very large and very robust,
    because eventually some very, very effective compounds will
    emerge there.
        And to go back to Dr. Bateman's point, one of the steps
    that could be taken in the clinical practice world is to
    implement and make widely available these diagnostic techniques
    so that patients who are potential participants in clinical
    trials could be identified much more easily than is currently
    the case without the use of biomarkers.
        I hope that helps answer your questions.
        Senator Toomey. Thank you. Thank you, Doctor. I see several
    of my colleagues have returned.
        So, Senator Carper, my understanding is you were not able
    to ask your questions the last time I handed it off to you. So
    if that is okay with you, I will hand it off to you again. I
    will go run and vote, and I see Senator Menendez has joined us,
    and maybe you could recognize him when you finish, if that is
    okay.
        Senator Carper. Yes. This is the second of the two votes,
    right, that you are going to?
        Senator Toomey. Correct.
        Senator Carper. I think this may be the last vote of the
    day.
        Senator Toomey. That is my understanding.
        Senator Carper. That is good. Okay. Good enough.
        Well, I tried to ask questions of the witnesses. They would
    not answer. They said they wanted to wait until you came back.
    [Laughter.] So we will go to this side. Thanks.
        Senator Toomey. All right; thank you.
        Senator Carper [presiding]. Let me say ``hi'' to everybody.
    I am Tom Carper from Delaware. And several of the folks who
    spoke, and the members and the witnesses, talked about how this
    is a family affair--Debbie Stabenow was saying it is a family
    affair.
        And in our own family, my mother, her sister, had dementia.
    My grandmother, their mother, had dementia. My great
    grandmother had dementia. And generally it was recognized in
    their late 70s, and my mom passed when she was about 83, and
    her sister almost the same age, maybe a year or two earlier. So
    this is something that we care about intensely and personally.
        I appreciate very much your work and its venues, and your
    willingness to be with us today. I want to--I am a person who
    likes to work out. I was a naval flight officer, a 21-year-old
    naval ensign in the Navy down in Pensacola, trying to become a
    naval flight officer. They put us through a really rigorous
    physical conditioning regimen. I was 22 when I left Pensacola,
    heading to Southeast Asia, and I was in great shape. I said,
    ``I am going to stay in shape as long as I can,'' and I have
    never stopped. I am 73 now, and I work out almost every day of
    my life.
        I tell people I cannot remember what I had for breakfast,
    but actually I can remember what I had for breakfast. And I try
    to eat really healthy foods as well. And where I am going with
    this is, in addition to--setting aside medicines and
    pharmaceuticals and so forth, therapeutics--in terms of
    lifestyle, the amount of sleep we get, the exposure to the sun,
    the food that we eat, have we learned that any of this helps,
    or not? If somebody could tackle that, I would be most
    grateful. I would like to start with that.
        Dr. Carrillo. Well, I am happy to start. This is Maria
    Carrillo. Thank you for that question, and for all of your
    support.
        We have actually found that much more research is pointing
    to the fact that there is a lot of dementia that is modifiable.
    And that is through changes in risk reduction, lifestyle
    changes like the ones that you have mentioned. I do the same
    thing. I try to work out as often as I possibly can in order to
    actually help my brain. And----
        Senator Carper. I also do it because exercise, as you know,
    rigorous exercise creates something called beta endorphin, that

    morphine-like substance that makes us feel good.
        Dr. Carrillo. And I think I feel sharper on those days
    because of all that is happening to benefit the brain through
    exercise. So it is crucial and it is important. We have seen
    results from the SPRINT MIND study, for example, studies funded
    by the National Institutes of Health that have shown us that
    even reducing your blood pressure to about 120, 125, has such
    an important benefit to the brain. And that study was so
    impactful in over 9,000 individuals. And that was without
    exercise. So imagine with exercise, nutrition, that impact
    could actually even be greater.
        That is why the Alzheimer's Association launched the U.S.
    POINTER study. It is going to look at four different modifiable
    risk factors to see if we can translate that into a public
    recipe that we can recommend. And we hope to work with the
    bipartisan BOLD Infrastructure for Alzheimer's Act, which
    became law in 2018, so that we can work together to advertise,
    to make public that risk reduction is one of the strategies
    that we should all be using. And through the Public Health
    Centers of Excellence, and funding through State, local, and
    tribal health departments, we hope to work together.
        As has been noted, one of the Centers of Excellence awards
    went to ourselves, and we are grateful for that opportunity to
    work with all of you. We continue to urge--AIM and the
    Alzheimer's Association both continue to urge all of you to
    fund next year's BOLD implementation act that provides the CDC
    the full $20 million authorized by the law in order to continue
    this important work. Because we have some answers now, we have
    to get them out to the public.
        Senator Carper. I agree. In terms of food, the diet, the
    kind of food that we eat and consume, is there anything there
    that is helpful in terms of risk reduction?
        Dr. Carrillo. Sure. I can share with you that----
        Senator Carper. Tell us chocolate is really great for risk
    reduction. [Laughter.]
        Dr. Carrillo. Chocolate, especially dark chocolate, has
    flavonoids and a lot of very good things for you, and I think
    it is always best--and I think my colleagues would agree--that
    we should eat all of those nutrients instead of taking a pill,
    for example, right, a nutritional supplement.
        However, if we think we cannot have access to one natural
    supplement or another, having a pill is certainly a good thing.
    But there is no evidence on any specific pill or nutritional
    supplement or nutraceutical that is actually beneficial for
    Alzheimer's. However----
        Senator Carper. What about blood pressure, which can be
    controlled by a pill?
        Dr. Carrillo. Correct. But I am talking about
    nutraceuticals, vitamins----
        Senator Carper. I understand.
        Dr. Carrillo [continuing]. Blueberries, eating those kind
    of things. We just know that antioxidants are good for you. All
    that is actually encompassed in several diets----
        Senator Carper. If we are what we eat, Maria----
        Dr. Carrillo. Correct. Yes. And the diet that we are using
    in our study, for example, is actually the Mediterranean Diet.
    So there are quite a few diets that have demonstrated some
    benefit, and we hope that the Mediterranean Diet--which is more
    leafy greens, more colored fruits and vegetables like
    blueberries, like kale, things like that, and less of the
    saturated fats, and less of the bleached carbohydrates like
    white flours, et cetera--is going to be more beneficial. But it
    is also not only for your brain; we have found that there are
    foods that are anti-inflammatory, which we know as a Nation is
    such a critical part of what happens in our brain not only as
    we age, but with disease.
        So all of this is telling us that food is so important to
    staying healthy with our heart, and of course with our brain.
        Senator Carper. Well, that is great. Lynn Sha, who is my
    legislative aide on health-care issues, is on the line with us,
    and she and I were talking on the phone the other day with
    Francis Collins, Dr. Collins, who heads up NIH, as you know,
    and we were getting a little bit of an update on the vaccines.
    You know, we have had two vaccines that have launched--one that
    has launched and one about to launch. And we have a couple of
    others in the wings--AstraZeneca in joint venture with Oxford
    in England, a couple with J&J as well. And what we have seen in
    response to COVID, I think is a collaboration that has been
    facilitated by NIH in large part.
        But you have pharmaceutical companies which oftentimes have
    competed against each other, not shared information, not
    collaborated, and in this instance they have been encouraged to
    collaborate and share information. And it has been possible to
    take a process from the beginning to actually having the
    vaccine that is safe to take, and instead of taking 5 or 10
    years, it has taken about a year.
        What lessons, if any, can we take from this process, this
    collaboration in developing the vaccine, that can help us
    shorten the time to actually get the help we need to get
    pharmaceuticals for dementia?
        Are there any lessons learned? I like to say, ``Find out
    what works and do more of that.'' Is there anything that we can
    take away from our success in going from idea to launch on a
    vaccine?
        Dr. Mohs. Yes, I think--this is Dr. Mohs--I think there are
    some things that we can learn. I mean, different players in
    this space--the pharmaceutical companies, the large companies,
    the small companies, the NIH, the FDA, et cetera--they all have
    different roles to play. And if there is somebody to facilitate
    communication and sharing of information among those to make
    sure that they are all playing their role, that just makes the
    process go faster because the information goes faster to the
    person or the group that can act on it more quickly.
        It is my understanding that also, though, there were some
    financial incentives that were put in place to make sure that
    some of the actors, or some of the participants in this--say
    the smaller companies that had very promising technology but
    maybe did not have the funds themselves internally to advance
    it rapidly through manufacturing and testing--that some
    financing was provided by the government. And I think that that
    helped that process go very fast, to allow even small companies
    that had promising technologies to move it very rapidly.
        Senator Carper. That is a good point. Anybody else on this
    point?
        Dr. Bateman. Yes. I just want to second what Dr. Mohs is
    saying and, Senator Carper, your point about finding out what
    works, what has worked before, to learn from it. Because I
    think something like a task force that would take the
    strategies that were used for COVID-19, these things can--some
    of them can be applied, I think, to the Alzheimer's problem.
        And just as Dr. Mohs said, I think there are ways for us to
    accelerate therapeutic drug development and bring more targets,
    more tests, more interventions into therapeutic trial
    development. The issue really is one of numbers, and trying to
    get enough treatments going in parallel that we increase the
    odds of finding highly effective treatments more quickly.
        And I think the urgency that was applied to COVID-19, the
    coordination that was applied, and the massive amount of
    support and fiscal resources that were applied have, directly
    led to that acceleration. We have seen this in our field
    already with increasing the budget of the NIH, the incredible
    growth in scientific understanding that has happened in the
    past 5 years, fantastic changes that have occurred in research.
    But I think we can continue to push this forward in a COVID-19
    urgency and make differences in Alzheimer's therapeutic trials.
        Senator Carper. That is great. Thank you.
        Dr. Dokholyan. Senator Carper, this is Nilolay Dokholyan.
    So I think one big area, again an untapped area, is industry/
    academia centers that would unite forces to tackle the problem.
    It is a cross-disciplinary problem where you have a lot of
    fundamental processes that require understanding, that need to
    be understood and translated to knowledge that can be used for
    drug discovery.
        And as such, I think facilitating cross-disciplinary
    research that connects, links scales across disciplines, would
    really promote development of the drugs and treatments.
        And NIH has already facilitated some of those kinds of
    translational research programs, and I know some companies have
    already created centers within universities. And I think
    incentives to create these kinds of centers that would combine
    efforts with representatives from both companies and academia
    working together, would really, I feel, facilitate the program.
        Senator Carper. All right; thanks. Thank you all.
        May I ask, Nikolay, where are you from? You have a great
    accent. Where are you from?
        Dr. Dokholyan. I am originally from Georgia--the Republic
    of Georgia, not Atlanta. [Laughter.]
        Senator Carper. The other day I was listening--I love
    music, and I have a service called ``Alexa,'' which allows you
    to tell your speakers, or whatever, to play music. And you
    would say, ``Alexa, play so-and-so.'' And I just happened to, I
    do not know why--I like Ray Charles, but I have not listened to
    Ray Charles for a long time, and I said, ``Alexa, play Ray
    Charles.'' And immediately I heard Ray Charles singing
    ``Georgia on My Mind.'' And we have two run-off elections there
    on January the 5th. So whoever wins is in the majority in the
    Senate. So----
        Dr. Carrillo. Senator, you just initiated my Alexa, so she
    started playing. Thank you. I had to tell her to stop.
    [Laughter.]
        Senator Toomey. That is the problem.
        Senator Carper, were you--did you have any more questions?
        Senator Carper. I do, but I have probably more than used up
    my time.
        Senator Toomey. All right, then, let me go to Senator
    Menendez.
        Senator Menendez. Well, thank you, Mr. Chairman. And let me
    thank all of our witnesses for being with us today and sharing
    your insights.
        This subcommittee held an Alzheimer's disease hearing last
    year, and the world is obviously quite different today than it
    was then. We are in the midst of a global pandemic that has
    upended everything. But in the midst of all this, I must say
    that I have been amazed by the innovation that has emerged in
    the past 9 months from new diagnostic tools and therapies to a
    vaccine that was approved last week.
        So if we as a Nation can innovate at such a rapid speed to
    defeat COVID-19, I think we can also put that energy into
    defeating Alzheimer's. And we have to be sure, however, that
    every American benefits from medical innovations. Even the most
    revolutionary new medicines are ultimately worthless if they do
    not reach the people who need them.
        So I believe we have to commit to ensuring that every
    American benefits from advancements in Alzheimer's diagnosis
    and treatment. And part of that includes improving clinical
    trial diversity.
        So let me ask Dr. Carrillo and Dr. Mohs--I have been
    working to engage pharmaceutical companies and other
    researchers to improve diversity in clinical trials.
        In your written testimony, you highlighted the need for
    increased participation by minority communities in Alzheimer's
    disease trials. How are your organizations working to address
    this urgent need? And what role can the Federal Government play
    to address this need?
        Dr. Carrillo. Well, I can start, and thank you, Senator,
    for that question. And it is nice to hear my name pronounced
    correctly, actually. Thank you very much for that.
        It is an important thing to study under-represented
    populations, so I will just speak for Latinos in particular. It
    is important that all my colleagues here, I think, recognize
    that not all Hispanic and Latin Americans can actually be
    painted with the same brush. We are all very different. And
    even recently, Dr. Hector Gonzalez at the University of
    California published some work from the SOL-INCA study, of
    course funded by NIH, highlighting that even the most well-
    studied to date risk factor gene, APOE-E4, does not confer the
    same risks on all the populations, depending of course upon
    their background.
        This is important. And so we need to really think about how
    we are going to invest in research that really highlights the
    importance of understanding diverse populations, especially if
    we are going to apply that to any kind of therapeutic or early
    detection diagnostics. So that is an important point.
        And we at the Alzheimer's Association are actually working
    very closely with the NIH on something that they have published
    recently, and are now currently revising, called ``Alzheimer's
    Disease and Related Dementias: Clinical Studies Recruitment
    Planning Guide and National Strategy for Recruitment of
    Participation.''
        Now, my organization in particular is working of course
    with the Federal Government, but we also have decided to put
    our money where our mouth is, and all clinical trials that we
    fund now require you, if you want our money, to ensure that you
    have diverse populations represented in those study populations
    you are recruiting.
        And that is an important point. On top of that, the U.S.
    POINTER study is shooting for 30-percent recruitment, and the
    new IDEAs platform, which is going to study 7,000 people with
    an amyloid PET scan, is requiring 2,000 black Americans and
    2,000 African Americans of those 7,000. So that is a majority.
        So that is what we are trying to do in order to ensure that
    when we do find those diagnostics and those treatments, they
    are actually for everyone. Thank you for the question, and for
    your efforts.
        Dr. Mohs. This is Dr. Mohs. Thank you for the question, and
    it is a pleasure to follow Dr. Carrillo and to address this.
        We have not been nearly as good as we should be in getting
    members of minority groups to participate in clinical trials.
    And as a result, the conclusions that can be drawn from those
    trials are still uncertain as to whether or not they apply to
    all segments of the population.
        So we need to fix this problem. The organization that I
    currently work with has taken two approaches. One is to try to
    bring members of the minority community, African Americans and
    Latinos, to clinical trial sites. And we have done a lot of
    things to try to do that, bringing in speakers who would
    resonate with members of minority groups, et cetera, and to
    some extent that has worked. It helps with engagement, but it
    has not always translated into enrollment in clinical trials,
    because interest does not necessarily lead people to want to
    volunteer. And there may be many reasons for that.
        A second approach is, we try to take the research centers,
    and the research activities, to the communities where African
    Americans and Hispanic patients reside. And I think ultimately
    that is likely to be more successful. Unfortunately, right now
    most of the clinical research centers are not located in the
    communities where those patients reside. So we have tried to
    take some steps to encourage health systems that serve
    primarily African American and Hispanic patients to become
    involved in research, and that may produce more salutary
    results.
        I do think that there is some value, as I mentioned in the
    written testimony, to ask FDA to provide clear guidance to
    sponsors on what they expect to see in terms of ethnic
    diversity in clinical trials. Because most commercial sponsors
    will respond to guidance from regulatory authorities. Thanks.
        Senator Menendez. Mr. Chairman, may I have one final
    question?
        Senator Toomey. Sure.
        Senator Menendez. Okay; thank you.
        With Latinos 1\1/2\ times more likely to develop
    Alzheimer's than their white counterparts, in your testimony,
    Dr. Mohs, you mention that we are not diagnosing enough people
    in the early stages of Alzheimer's, when they might still be
    candidates for a trial.
        In lower-income communities, there remain many barriers to
    assessing an appropriate diagnosis of Alzheimer's, let alone an
    early one. What can be done to improve access for patients in
    under-served communities to ensure they are able to access
    resources and information, and be eligible for these clinical
    trials?
        Dr. Mohs. Yes; thank you. As I also mentioned in the
    written testimony--and as was discussed by some of the other
    participants--we are making substantial progress in what I hope
    will be low-cost, potentially widely available blood-based and
    digital biomarkers that will assist in the early diagnosis, and
    may make it possible to make very clear diagnoses without the
    time-consuming and expensive and highly specialized resources
    that are now required to make the diagnoses earlier.
        Those technologies, the blood-based simple ones, which
    could be very inexpensive, are advancing. I think we need
    additional support to do further clinical research to
    understand exactly how good they are, and how they should be
    applied in conjunction with other things in clinical practice.
    And there need to be some incentives, financial incentives,
    through insurance and health-care reimbursement systems, to
    make sure that clinicians are reimbursed for using those tests.
        Senator Menendez. Thank you, Mr. Chairman. Thank you.
        Senator Toomey. Thank you.
        Senator Young?
        Senator Young. Well, thank you, Mr. Chairman, for holding
    this important hearing.
        This question is directed to all members of the panel who
    would like to address it. What lessons can we learn from the
    successful public-private partnership between the industry on
    the one hand, and BARDA on the other, during COVID-19? Is a
    similar approach needed here, given the pandemic-like scale of
    Alzheimer's disease?
        Dr. Bateman. Senator Young, I might start with that. We
    have a public-private partnership trial platform running in
    Alzheimer's disease of a very special kind. It is an early-
    onset--it is called autism undominant, and it is caused by
    mutations in families that inherit these mutations, and it
    causes Alzheimer's disease.
        And when we began that, 12 pharmaceutical companies came
    together in a consortium and, with support from the Alzheimer's
    Association, the National Institutes of Health, and our
    pharmaceutical partners, we launched one of the first
    prevention trials for Alzheimer's disease, testing more than
    one therapy at a time.
        And in this parallel approach, we were able to accomplish
    things that I do not think would have been possible without
    that public-private partnership. And so I think, as we have
    said throughout this meeting, that COVID-19 offers many
    opportunities to look towards efficiencies and ways to get
    things done quickly, and this is one more way to do this.
        I do believe that a public-private partnership for
    therapeutic development, one that focuses on preventable
    trials, focuses on multiple shots on goal, focuses on bringing
    forward a variety of therapeutic approaches, is consistent with
    what NAPA had outlined to be a goal of an effective treatment
    or a cure by 2025.
        I think the other panelists here can speak to a lot on
    public-
    private partnerships, and I would be happy for them to say more
    about this, because it really is a promising approach that can
    enable things to happen that otherwise would not be possible.
        Senator Young. Dr. Mohs?
        Dr. Mohs. Yes, I can follow on to Dr. Bateman's comments
    here. In the development of therapeutics, there are many
    players that are required. There are large pharmaceutical
    companies, small companies, the NIH, the FDA, et cetera, and
    they each have their own skill sets and things that they can do
    well. But the amount of drugs that come through, the treatments
    that eventually come through, require all of those participants
    to do the activities that they are good at, and do them quickly
    and in coordination.
        One role that I understand the Federal Government has
    played in the development of COVID-19 vaccines and therapeutics
    is to provide coordination of the activities of the different
    actors in this ecosystem, maximizing the utilization of the
    skill sets that they have. So that is one role.
        The second is that, where there is one of the potential
    participants--say a small company that has technology that
    could play a critical role--that may not have the financial
    resources to make that resource as productive as it can be,
    they have then stepped in, as I understand it, to provide some
    financial resources to allow that entity, usually a commercial
    entity, to maximize the use of their technologies.
        So I think those are two roles that the Federal Government
    can play to speed up this whole process of moving potential
    therapies through the pipeline and to patients.
        Senator Young. Thank you. I am going to move on, and there
    may be an opportunity on the back end to add to that, if others
    would like to.
        Dr. Dokholyan, you described how a deeper integration of
    the private sector with academia could provide new solutions in
    the drug pipelines for neurodegenerative diseases. Could you
    elaborate on this idea of deeper integration between academia
    and the private sector, and describe how private partnerships
    with academic institutions could be fostered?
        Dr. Dokholyan. Thank you for this question. Naturally,
    companies are driven by investors' interests and will evolve to
    optimize expenditures and drive discovery. But the dominant
    part, in this case especially, is the basic research, which is
    often invisible to investors. Therefore, one way to mitigate
    this is to move the exorbitant R&D costs of pharmaceutical
    companies, or of technological companies, and to outsource them
    to academia more, or rather, create centers that would actually
    focus academic research on a particular problem of interest, in
    this case Alzheimer's research.
        And in this case, it is not only that the companies can
    work together with academia, but also associations. And the
    Alzheimer's Association is doing a great job. But I want to
    bring attention--I have been working on protein misfolding
    diseases for a while, and I have worked on cystic fibrosis. And
    the Cystic Fibrosis Foundation, I think--it was really a huge
    breakthrough that they have developed a drug for one case of
    cystic fibrosis. But that was a success story to me, this deep
    integration of all of these moving pieces together. And what
    government can do is to incentivize companies to invest in
    academia and go forward with that.
        If I may add, I think there is another thing that is
    missing here, which is training. The problem is that, as I
    mentioned, the disease is cross-scale. It is multi-scale, has
    multi-scale origins. And so as such, we are dealing basically
    with molecules, with cells, with organisms, with populations,
    and we have niches for science to deal with that. But we need a
    new breed of scientists that will be able to, while
    specializing in their own field, have the vision outside and
    see beyond.
        And that is the translational research. NIH has been really
    behind that initiative, but I think we do need a bigger push in
    that direction to facilitate scientists of that thought.
        So, thank you.
        Senator Young. Thank you, Doctor.
        Dr. Mohs, in your testimony you encourage greater
    collaboration between FDA and CMS. How would increased FDA and
    CMS collaboration help patients access diagnostics or therapies
    sooner?
        Senator Toomey. And if we could maybe try to sum this up
    quickly, because we are well over time here.
        Senator Young. My apologies.
        Dr. Mohs. The basics are that for a commercial sponsor,
    somebody who is developing a product which is intended to be
    either a therapeutic or a diagnostic, they need to know the
    path for regulatory approval, which goes through the FDA. And
    generally the FDA is pretty good about giving guidance as to
    what they expect to make a thorough evaluation. But
    particularly in the area of diagnostics, the path to
    reimbursement is uncertain. And even if you may have an
    effective diagnostic, if it's not reimbursed, it is not going
    to be widely available to patients, and it is not going to be
    able to enable clinicians to improve patient care or to enroll
    patients in clinical trials.
        So I think that parallel review of both the standards for
    regulatory approval through the FDA, and for reimbursement
    through CMS, would speed this process.
        Senator Toomey. Thank you, Dr. Mohs.
        Senator Warner?
        Senator Warner. Thank you, Mr. Chairman. I want to just
    make a quick comment first, referring back to Senator
    Menendez's points about health-care disparities. I know the
    Latino population is 1\1/2\ times more likely to develop
    Alzheimer's, and the African American population, two to three
    times more likely.
        One practice we started in Virginia was a technology-based
    solution to get people into these trials called a ``senior
    navigator,'' where we would train some--we created a Statewide
    site with all assistance to senior programs, Alzheimer's and
    otherwise related, and would go either through a church or
    through a senior center and usually train at least one healing
    front-end navigator that could then access these sites, access
    diagnosis, access getting into trials.
        I appreciate the panel's comments about trying to make sure
    that we get the appropriate patient mix, with the disparate
    effects on minority communities.
        My question--and again, let me thank the whole panel. I am
    sure others have their own personal stories. My mom had
    Alzheimer's for 11 years, 9 years of which she did not speak.
    My father and sister took care of her at home until the last
    few weeks. I could not imagine having taken on that challenge.
    So something I have been working on since I was Governor and
    throughout my time in the Senate is on advanced care planning
    in bipartisan legislation. I think Senator Stabenow raised this
    issue earlier.
        I would just like to have the panel speak to this: how we
    can do a better job of this team-based approach for families to
    treat
    Alzheimer's-related patients who sometimes cannot make these
    decisions if they do not do that planning early enough with
    their loved ones, with their religious counselor, with an
    appropriate medical professional--whether it is around advanced
    directives and allowing those advanced directives to move
    easier from State to State; whether we can make sure that we
    have, frankly, better reimbursement for some of these types of
    discussions and conversations. Most families do not like to
    have these end-of-life discussions.
        And I would just like to have the panel speak to each point
    individually. In this area, it has been harder to move than I
    would have thought, because it is clearly bipartisan. But where
    do you feel the state of advanced care planning stands, both
    legislatively and in terms of new directives?
        And that will be my only question, Mr. Chairman.
        [Pause.]
        Senator Warner. Panel, who wants to go first?
        Dr. Mohs. Well, this is Richard Mohs. I can try to go
    first, and I am maybe not the most qualified person on the
    panel to address this, but years ago I used to see quite a
    number of patients, back when I worked in a hospital, and a new
    diagnosis of dementia is an overwhelming experience for
    patients and families.
        They have a hard time coming to grips with it,
    understanding its full implications, and oftentimes the medical
    system, the way it is currently constituted, is not very good
    at helping them step through all the decisions that they are
    going to have to make once they get the diagnosis.
        I do think on the technology side, the discussions we have
    been having around advances in early diagnosis, and the
    certainty that that can provide about what is going on with a
    patient, may allow patients and their families much more time
    to begin this process of planning and allow them to begin the
    process at a time before the patient is severely impaired, so
    that the patient can participate in the planning process and
    make their wishes very well-known.
        I think it would also be helpful if there could be some
    mechanism to institute model care plans that include things
    like instructions on how to do advance directives of various
    types that would be geared toward people of different
    backgrounds, different financial means, et cetera. And there
    probably is a role for States and the Federal Government in
    developing those model plans once we have earlier diagnosis
    being much more common in the community.
        Senator Warner. Any other panelists? I know the chairman
    wants to move on, but are there any other panelists who would
    like--I know you are more on the research side, but----
        Dr. Carrillo. Well, I will be able to--Senator, thank you
    very much for the question. I think that is why the Improving
    HOPE for Alzheimer's Act is so important, because it would more
    than ensure that providers have the awareness of, not only
    codes that they have to use, but how to use them and how then
    they actually help the families to maneuver and get through
    that complicated process.
        The online navigator sounds fantastic, but the bottom line
    is that helping people to navigate through that advanced care
    planning that has to happen, through how to ensure they
    understand all of the different aspects of their health care
    that actually comes to bear on the diagnosis of dementia that
    they experience with their loved one, is so important. And so,
    in absence of a treatment, we have to actually make sure we do
    all we can to ensure that quality care and quality of life are
    actually most prominent and important for all of us. So, thank
    you very much.
        Senator Warner. I will cede back my time. I will just say
    we have made some progress on making sure the health-care
    provider gets some reimbursements. I do think it is critical
    that we do that. We will spend plenty of money on reimbursing,
    diagnosing, or prescribing meds. We do not have that kind of
    most difficult of all conversation that needs that health-care
    provider's input, time, and effort.
        Thank you, Mr. Chairman. Thank you for holding this
    hearing.
        Senator Toomey. Thank you, Senator Warner.
        Senator Cassidy?
        Senator Cassidy. Hey, everybody. I apologize. I was on
    another conference call, so if I am asking questions that
    others have, I apologize.
        Dr. Bateman, I will start with you. I have read that since
    Down syndrome children and adults have an incidence of
    Alzheimer's that has earlier onset, this kind of gives a model,
    if you will, to follow folks. And maybe it would show insights
    into the genetic basis of this, and interventions. And I
    understand there is a study doing this. Can you comment on that
    study? And has it given us any information which is helpful?
        Dr. Bateman. Yes. There are actually several studies
    underway which are looking at Down syndrome, or trisomy 21, to
    better understand the risk of Alzheimer's disease in those
    individuals.
        It is actually one of the foundations of current
    Alzheimer's theory and research. The discovery that people who
    carry this extra chromosome--and later we found out that it was
    a certain part of the chromosome that encodes a protein called
    amyloid precursor protein--is one of the pieces of evidence
    that amyloid can be an essential and necessary, although not
    sufficient, factor that leads to Alzheimer's.
        The other is families that we study in our research studies
    of dominantly inherited Alzheimer's, these mutations that alter
    amyloid's processing. The animal models that have developed
    therapeutics that are now in clinical trials testing for
    amyloid have largely been built on these findings, and our
    current generation of treatments was built on those factors.
        The Down syndrome studies are revealing other factors that
    we think are important in Alzheimer's disease. There were
    several funded through the NIH. There are funded studies in
    Europe and in other places that are continuing to add to the
    information.
        I would just comment that all of this has to do with the
    foundation of basic science that then leads to translational
    research that----
        Senator Cassidy. Dr. Bateman, I need to interrupt, because
    I have only about 2 minutes left.
        Dr. Carrillo, now clearly though, we have this genetic
    basis just described by Dr. Bateman, but there are also these
    risk factors that have a dominant role.
        Now we read about PET scans showing somebody has amyloid--I
    am told there are studies out there that, if somebody has a PET
    scan showing that they have amyloid deposition, there is a high
    frequency of adjustments to their medical regimen within 90
    days of that discovery.
        So it is a duality, right? It is the amyloid, and it is the
    lifestyle. Is anything being done, for example, in MA plans
    that would reward them to attempt to make an early diagnosis of
    Alzheimer's? Or are there any projects that you know of that
    would, on a clinical scale, implement this screening for
    amyloid to allow this adjustment of lifestyle factors? You can
    probably phrase the question better than I, but I think you
    know what I am going after.
        Dr. Carrillo. That is a great question. We do have the
    IDEAs Study that has demonstrated that there is a definite
    change to patient care within 90 days of having a positive PET
    scan. And that can go both ways. You can test negative, so you
    have some other type of dementia, or you can test positive and
    you will definitely have Alzheimer's, so let us see what we can
    do about it and treat it properly.
        But you are talking about risk factors, and we are
    currently launching the U.S. POINTER study that includes
    imaging. So the U.S. POINTER study is paid for and led by the
    Alzheimer's Association and academic sites across the country.
    It combines four modifiable risk factors, and we will try to
    slow cognitive decline in the aging at-risk population.
        Thanks to the NIH and additional dollars at the National
    Institute on Aging, we are adding imaging, amyloid and tau, to
    see if we can correlate changes in our behavior, changes for
    reducing our risks, with those changes that are the hallmarks
    of----
        Senator Cassidy. Let me ask you. At some point, end organ
    damage has been done, and so modifiable risk factors then
    become less capable of modifying the end organ. So do we know
    if there is an age at which we really--you know, there is going
    to be some tradeoff, right? Somebody with clear clinical
    Alzheimer's will have a positive PET scan that does not help
    us.
        We want to move back, probably before Medicare age. So
    please comment on that.
        Dr. Carrillo. Correct. And that is why these individuals
    are 60 and over, and at risk. They do not have dementia
    currently. So we are trying to see if we can modify things and
    measure those early markers, to measure amyloid and tau
    earlier, before you have dementia. So if you can actually
    modify those things, can you stop that cell death, that nerve
    degeneration that actually is the start of the cognitive
    decline?
        Senator Cassidy. And so that is the whole--let me ask you
    one more thing, because I am out of time. To what degree could
    you move that earlier than 60? Because intuitively, if you find
    somebody at risk at age 50, you have more time to do the
    lifestyle modification, et cetera.
        Dr. Carrillo. You absolutely can, and there are some
    studies that are actually going on that are going much earlier,
    at 45. Certainly Randy Bateman's with the Down inherited are
    going even earlier. We start at 60 because we want, at least in
    5 years, a glimmer of hope of seeing a change. So that is why
    we are starting at 60. But absolutely, yes.
        Senator Cassidy. Okay; I am over time. I yield back. Thank
    you, Mr. Chairman.
        Senator Toomey. Thank you, Senator Cassidy.
        Senator Cantwell, you are recognized for 5 minutes.
        Senator Cantwell. Thank you, Mr. Chairman. Can you hear me?
        Senator Toomey. Yes.
        Senator Cantwell. Thank you so much for holding this
    important hearing. And thank you so much for yours and Senator
    Stabenow's work in this area.
        I wanted to ask Maria Carrillo about the Allen Institute
    work on brain science as it relates to Alzheimer's, and what
    you think we have learned from that information thus far, and
    what additionally do you think we should be doing to follow up
    with that research?
        Dr. Carrillo. Thank you for the question, Senator Cantwell.
    The Allen Institute--and we have visited and actually
    collaborated with them as well--is a fantastic institute that
    creates tools for basic scientists on the importance of really
    understanding, really the miraculous brain at the animal level,
    and I think they are venturing also now into human brains.
        And that is such an important thing because, as you have
    already heard through earlier testimony, so many of the
    underlying causes of brain dysfunction are unknown. But you
    know, even more so sometimes we do not even understand how the
    brain does the miraculous things it actually does when it
    works. So that is why it is so important to have this type of
    work continue.
        Now the only suggestion I would have is that it is
    important for what they are doing at the Allen Institute to
    then penetrate into additional human work in clinical trials.
    And that means working with industry and making sure that those
    scientists understand what is happening there; continuing to
    work with us and other government groups to get that word out.
        But that is a very important institute for the science.
        Senator Cantwell. Well, I think the thing that I am
    interested in--and obviously, I appreciate the chairman
    mentioning it in his opening statement--about the goal of
    finding a cure, I think was the word he used, is the timeline
    that was set out.
        I think we have to ask ourselves an important question: how
    many Americans are truly affected by this? And how many more in
    the bow waves of baby boomers reaching retirement are going to
    be affected by this? And what is that exponential cost?
        And I think the Allen Institute, when they distinguish
    markers, brain markers that might be indicators, the question
    becomes, what kind of testing, what kind of analysis could we
    do that would apply that to the broader public?
        I think we are seeing a bow wave of costs coming at the
    Federal Government on this issue. I have hope that the chair is
    right, and we will meet that goal and timeline, but I am
    telling you that we really need to analyze these numbers. And I
    think we are going to see how important it is for us to really
    get even more specific about our goals, our accomplishments,
    and how to continue to zero in on this, because I just think
    that it is impacting way more people than people realize.
        Thank you, Mr. Chairman.
        Senator Toomey. Thank you, Senator Cantwell. And I think
    that covers all of the Senators who have attended this hearing.
        Senator Stabenow, did you have a comment you wanted to make
    here at the close?
        Senator Stabenow. Well, thank you, Mr. Chairman. I did.
    Once again, I am sorry for the technology of losing the video
    here where I am, but I have listened to all of the testimony
    and the questions, the very thoughtful questions.
        And to follow on Senator Cantwell, there is no question
    that we know right now 1 out of every 5 Medicare dollars is
    connected to Alzheimer's. And that is only going to go up. So I
    appreciate all the thoughts from the discussion on therapeutics
    and diagnostics.
        I would just emphasize again the importance of supporting
    families and caregiver planning, and having SAMHSA really
    implement a strong education outreach campaign to ensure
    providers are aware of the new reimbursement for caregiver
    planning sessions--and that families are as well--and that
    ultimately we develop some alternative payment models that
    really focus on managing Alzheimer's and quality of care and so
    on as we reach for the cure, which is what we all want.
        So thank you, Mr. Chairman.
        Senator Toomey. Thank you, Senator Stabenow. And I really
    want to sincerely thank each and every one of our witnesses
    today. Your testimony was really very, very interesting, and
    informative, and helpful. As we strive for a cure, or an
    effective therapy by 2025, I think it is clear--and was made
    clear during our conversation today--that the Federal
    Government, the scientific community, and the private sector
    all need to work together to gain a better understanding of
    this disease, and further reduce the barriers that remain to
    the research and the development that we have discussed here
    today.
        Please be advised that members will have 2 weeks to submit
    written questions that can be answered later in writing. Those
    questions and your answers will be made part of the formal
    hearing record.
        And with that, this subcommittee stands adjourned. Thank
    you.
        [Whereupon, at 4:26 p.m., the hearing was concluded.]

                                A P P E N D I X

                  Additional Material Submitted for the Record

                                  ----------

     Prepared Statement of Randall J. Bateman, M.D., Charles F. and Joanne
     Knight Distinguished Professor of Neurology; and Director, Dominantly
       Inherited Alzheimer's Network (DIAN), DIAN Trials Unit (DIAN-TU),
                    Washington University School of Medicine
        Chairman Toomey and Ranking Member Stabenow, members of the
    committee, I want to thank you for the opportunity speak today on the
    important topic of Alzheimer's disease and advances in medical
    diagnosis and treatment. Alzheimer's disease is one of the greatest
    medical challenges facing patients, families, the medical community,
    and society due to its immense personal and financial impact. We must
    stop this disease as outlined in the National Alzheimer's Project Act.
    Recent advancements in our understanding of the disease, our ability to
    detect, track, and diagnose the disease in research and the clinic, and
    drug development which can stop and reverse some of Alzheimer's disease
    pathologies hold promise to meet our shared goal of ending Alzheimer's
    disease. This is due in large part to the Senate's support of the NIH
    and long-term investments in research and training talented
    investigators.

        We have come a long way in our understanding of the disease, our
    ability to detect, track, and diagnose Alzheimer's in research and the
    clinic, and development of drugs which can stop and reverse some of
    Alzheimer's disease pathologies. We have specific tests that can
    identify the two key pathologies of Alzheimer's, amyloid plaques and
    tau tangles, in brain scans, cerebrospinal fluid, and now in the blood.
    Treatments targeting amyloid plaques can remove these plaques to
    undetectable levels, something that wasn't possible just a few years
    ago. We are learning from clinical trials how to dose these medications
    more effectively and who are likely to benefit from them. Based on
    recent trials, we think patients early in the disease process when they
    have Alzheimer's disease pathology but don't yet show clinical
    symptoms, may benefit the most from a preventive approach to targeting
    the disease. The first generation of Alzheimer's prevention trials have
    been launched, and initial results show that we are getting closer to
    maximizing drug effects and approaching the goal of delaying and
    ultimately stopping the onset of Alzheimer's disease. A potential
    strategy to achieve this in the general population is using highly
    sensitive and accurate measures of the disease, for example blood
    tests, to first identify those who have Alzheimer's disease pathology
    and are at high risk of progressing to dementia. We would then treat
    these individuals with drugs to halt and reverse the Alzheimer's
    process in the brain before significant and irreversible brain damage
    occurs. The tools are now at hand to implement this strategy in large-
    scale prevention trials.

        However, there are clear barriers to developments in the
    diagnostic, therapeutic, and research pipelines for Alzheimer's
    disease, and new Federal strategies could enable breakthroughs in the
    disease's diagnosis and treatment, similar to what has been
    accomplished for diagnostics and vaccines for the COVID-19 pandemic.
    Summarized below are some of the ongoing challenges, and the associated
    opportunities that could greatly accelerate the discovery and
    validation of Alzheimer's disease treatments and preventions:

          (1)  Barriers to therapeutic development

              a.  Regulatory burden, risk-averse trial designs, and
    sometimes lack of urgency and not accounting for the costs of inaction
    lead to clinical trial delays and higher overall costs. Because
    Alzheimer's progresses over years until dependence on others for care
    and eventually death, Alzheimer's disease trials are long. Extensive
    international regulatory reporting requirements and approval delays
    cause major trials to cost several hundred million dollars and take 3
    to 5 years to complete, while prevention trials are even longer (about
    7 years). These trials are too expensive and too long, causing
    potential treatments to be ``left on the shelf'' untested, and some
    drug developers to abandon Alzheimer's drug development programs. In
    order to implement large scale global trials, the field needs to move
    quickly and test more drugs in parallel, creating more ``shots on
    goal.''

              b.  If regulations could be made more facile and appropriate
    incentives made (for example, incentivizing and enabling faster trials
    similar to COVID-19 treatment development), then accelerated
    development would occur and lead to faster treatment development. This
    is an urgent issue--there is a tsunami of at-risk people (estimated at
    5 million in the U.S.) who could be spared Alzheimer's disease--if we
    can develop treatments and preventions in time.

              c.  How can this be helped? Policy-makers and agencies can
    enable and support standards which: (1) account for the personal and
    financial cost of Alzheimer's disease in terms of the opportunity costs
    of delays into decision making (i.e., a balanced risk-benefit analysis
    accounting for time lost on deliberations); (2) enable science and
    medicine to advance at optimal speed, accounting for potential benefit
    while managing risk; and (3) encourage investment in the development of
    treatments and preventions for Alzheimer's disease.

        (2)  Diagnostics

              a.  Highly accurate diagnostic measures of Alzheimer's
    disease amyloid plaques and tau tangles have been available for a
    number of years, and more recently, simple blood tests have been
    developed, but they are not used in clinics yet for several reasons,
    including lack of payer support. Symptomatic patients and their doctors
    have a need to know an accurate diagnosis. These tests can accurately
    identify who has Alzheimer's disease, and importantly, who does not
    have Alzheimer's disease. Because about 50 percent of Alzheimer's
    disease is not accurately diagnosed through a clinical assessment
    alone, testing for pathology would provide specific and accurate
    treatment to those with Alzheimer's, while informing the physician to
    investigate other causes if problems with memory and thinking are not
    due to Alzheimer's disease. Because some of the causes (e.g.,
    depression, medication side effects, thyroid disorders, etc.) are
    treatable or reversible, it is important to have an accurate diagnosis.
    We must identify the disease in order to treat and manage it.

              b.  For research purposes, measurable indicators of
    Alzheimer's disease pathology (biomarkers), such as blood and
    cerebrospinal fluid amyloid and tau, offer immense promise. These
    biomarkers are being used to screen for the disease, track the effects
    of treatments on Alzheimer's disease biological processes, and are also
    being considered for surrogate biomarker development, which would
    greatly speed Alzheimer's disease trials.

              c.  When preventions are developed, screening biomarkers will
    be essential to identify those on the Alzheimer's path to appropriately
    treat those with high risk.

                                     ______

                 Prepared Statement of Maria Carrillo, Ph.D.,
                 Chief Science Officer, Alzheimer's Association
        Chairman Toomey, Ranking Member Stabenow, and members of the
    committee, my name is Maria Carrillo, and I serve as the chief science
    officer of the Alzheimer's Association. Thank you for holding this
    important hearing today and for the opportunity to testify on the
    Alzheimer's and other dementia therapeutic and diagnostic pipelines,
    and on the Federal policies that will help address barriers to foster
    much-needed breakthroughs in diagnosis and treatment.

        Founded in 1980, the Alzheimer's Association is the world's leading
    voluntary health organization in Alzheimer's care, support, and
    research. The Alzheimer's Association is the nonprofit with the highest
    impact in Alzheimer's research worldwide and is committed to
    accelerating research toward methods of treatment, prevention, and,
    ultimately, a cure. The Alzheimer's Impact Movement (AIM) is the
    advocacy arm of the Alzheimer's Association, working in strategic
    partnership to make Alzheimer's a national priority. Together, the
    Alzheimer's Association and AIM advocate for policies to fight
    Alzheimer's, including increased investment in research, improved care
    and support, and development of approaches to reduce the risk of all
    dementia.

        Alzheimer's is a progressive brain disorder that damages and
    eventually destroys brain cells, leading to a loss of memory, thinking,
    and other brain functions. Ultimately, Alzheimer's is fatal. We have
    yet to celebrate the first survivor of this devastating disease.

        In addition to the suffering caused by the disease, Alzheimer's is
    also an enormous strain on the health-care system, on families
    including my own, and Federal and State budgets. Alzheimer's was
    projected to be the most expensive disease in America in 2020, with
    costs set to skyrocket at unprecedented rates. While there are over 5
    million Americans currently living with the disease, without
    significant action, nearly 14 million Americans will have Alzheimer's
    by 2050. In 2020, Alzheimer's and other dementia will cost the Nation
    $305 billion, including $206 billion in Medicare and Medicaid payments.
    Unless a treatment to slow, stop, or prevent the disease is developed,
    in 2050, Alzheimer's is projected to cost more than $1.1 trillion (in
    2020 dollars).
                             barriers to pipelines
    Medical Research
        We have seen great scientific progress with the historic funding
    increases Congress has made in Alzheimer's and related dementia
    research at the National Institutes of Health (NIH). In fact, since
    Congress passed the National Alzheimer's Project Act (NAPA) 10 years
    ago, Alzheimer's NIH research funding has increased more than sixfold.
    This investment has been critical to progress toward the primary
    research goal to effectively treat and prevent Alzheimer's by 2025,
    including advances into new biomarkers to detect the disease.

        Biomarkers offer the most promising paths because they can detect
    the earliest brain changes. The Food and Drug Administration (FDA) has
    approved positron emission tomography (PET) scans to identify the
    hallmark amyloid plaques and tau tangles in the brain and is currently
    reviewing an application for cerebrospinal fluid (CSF). We are also
    closer to a blood test for Alzheimer's than ever before: breakthrough
    research presented at the Alzheimer's Association International
    Conference (AAIC) 2020--the largest convening of dementia scientists in
    the world--this past July found that specific markers in the blood may
    be able to detect changes in the brain 20 years before Alzheimer's
    symptoms occur. These biomarkers will be new diagnostic tools in the
    toolbox for primary care doctors and specialists to assist in the early
    and more accurate diagnosis of Alzheimer's. In addition to these great
    advances, there is a drug under review at FDA, for the first time, that
    may treat the underlying biology of the disease.

        However, even with these great strides, there is still much left to
    be done. Investment in Alzheimer's research is still only a fraction of
    what's been applied over time to address other major diseases. Between
    2000 and 2017, the number of people dying from Alzheimer's increased by
    145 percent while deaths from other major diseases have decreased
    significantly or remained approximately the same.

        Alzheimer's is one of the most complex challenges science and
    medicine has ever faced. The reality is that we don't yet know as much
    as we would like to about the underlying causes of Alzheimer's,
    compared to some other major diseases. It is a heterogeneous disease,
    marked by the accumulation of beta-amyloid plaques and tau tangles in
    the brain, and neurodegeneration. We are still learning about other
    brain changes such as inflammation, changes in the way our brain cells
    process energy and nutrients, the role of the immune system and how our
    brain cells communicate. This heterogeneity underscores the need for
    diversification of research targets. Funding diverse avenues of
    investigation and understanding the causes of the disease will
    ultimately enable us to discover effective Alzheimer's diagnostics and
    treatments.

        It is critical to note that while the field of Alzheimer's
    biomedical research has made great gains over the years in
    understanding the brain changes associated with the disease and how the
    disease progresses, much of the research to date has not included
    sufficient numbers of blacks/African Americans, Hispanics/Latinos,
    Asian Americans/Pacific Islanders, and Native Americans to be
    representative of the U.S. population. Studies indicate that older
    blacks/African Americans are about twice as likely to have Alzheimer's
    or other dementia as older whites. Some studies indicate older
    Hispanics/Latinos are about one and one-half times as likely to have
    Alzheimer's or other dementia as older whites. However, Hispanics/
    Latinos comprise a very diverse group in terms of cultural history,
    genetic ancestry and health profiles, and there is evidence that
    prevalence may differ from one specific Hispanic/Latino ethnic group to
    another, for example Mexican Americans like myself, compared with
    Caribbean Americans. Moreover, because blacks/African Americans and
    Hispanics/Latinos are at increased risk for Alzheimer's, the
    underrepresentation of these populations not only hinders the ability
    of researchers to understand these health disparities, it also
    restricts their knowledge of how an approved therapy or diagnostic may
    affect the population most likely to need the drug.

        Current and future Alzheimer's research must include greater
    numbers of underrepresented populations in clinical trials,
    observational studies, and other investigations to ensure everyone
    benefits from advances in Alzheimer's science. In order to increase the
    recruitment and retention of these populations, researchers must
    understand how to foster and maintain partnerships with trusted
    community-based organizations, ensure that members of their research
    team reflect underrepresented groups, and budget adequately for
    recruitment and retention efforts. These strategies are outlined in the
    National Institute on Aging's Alzheimer's Disease and Related Dementias
    Clinical Studies Recruitment Planning Guide and National Strategy for
    Recruitment and Participation in Alzheimer's and Related Dementias
    Clinical Research. Congress should prioritize policies that will help
    apply these strategies, and others, to increase the participation of
    underrepresented populations in Alzheimer's clinical trials. The
    Alzheimer's Association and AIM look forward to working with the
    committee and other congressional members to accomplish this.

        It is crucial that we continue to increase investment in research
    in order to maximize every opportunity for success. This will enable us
    to learn all of the ways Alzheimer's affects the brain, develop better
    diagnostics, and discover effective treatments for the disease. The
    Alzheimer's Association and AIM urge Congress to finalize an additional
    $354 million for NIH Alzheimer's funding in fiscal year (FY) 2021,
    which was included in the recent Senate draft. We cannot afford to
    leave any stone unturned. With every study, we are illuminating the
    biology of Alzheimer's and finding another piece of the Alzheimer's
    research puzzle.
    Coverage of Diagnostics
        With all of the scientific progress researchers are making in the
    field of Alzheimer's biomarkers, we need to ensure there is access to
    these diagnostic tests. Coverage for diagnostics would help spur
    private-sector engagement on both diagnostics and therapeutics.

        Diagnostic testing with a validated biomarker for Alzheimer's is
    critical. Even in the absence of a treatment, early and accurate
    diagnoses allow individuals to plan, participate in clinical trials,
    and express preferences to friends and family. The Alzheimer's
    Association has worked with the Centers for Medicare and Medicaid
    Services (CMS) since 2013 to explore coverage of amyloid PET scans,
    resulting in the IDEAS Study, of which I am a co-chair. The IDEAS Study
    seeks to gather evidence to support reimbursement by Medicare and third
    party payers to determine if amyloid PET scans can help clinicians
    accurately diagnose the cause of cognitive impairment, provide the most
    appropriate treatments and recommendations, and improve health
    outcomes. Building on what we have learned from IDEAS, we are now
    partnering with CMS to launch New IDEAS, which will study the impact of
    amyloid PET scans on more diverse and historically underrepresented
    populations.

        The IDEAS Study demonstrated amyloid PET scans changed medical
    management in nearly two-thirds of cases, demonstrating that PET
    imaging can be a powerful tool to improve the accuracy of the causes of
    cognitive impairment, including Alzheimer's diagnosis, and lead to
    better medical management, especially in
    difficult-to-diagnose cases. If a treatment that addresses the
    underlying biology of the disease were to become available, accurate
    diagnostic testing would be a crucial first step in determining
    appropriate access to the drug. Additionally, the increasing
    availability of therapeutics in the coming years will also raise the
    awareness of Alzheimer's and other dementia and drive the public's
    desire for assessment. Our health care system, including the FDA and
    CMS, must be prepared to evaluate and provide coverage of these
    assessment and diagnostic services.
    Clinical Practice Guidelines
        Despite more than 2 decades of advances in diagnostic criteria and
    technology, symptoms of Alzheimer's disease and other dementia too
    often go unrecognized or are misattributed. This causes delays in
    accurate diagnoses and appropriate care that are harmful and costly.
    There currently are no consensus Alzheimer's diagnostic recommendations
    for primary care physicians. Guidelines were created some years ago but
    were only developed for neurologists.

        As reported at AAIC 2018, a work group convened by the Alzheimer's
    Association under leadership by Dr. Bradford Dickerson, Dr. Alizzera
    Atri, and I developed 20 recommendations for physicians and nurse
    practitioners to provide practical and specific U.S. guidelines that
    are relevant to both primary and specialty settings. The
    recommendations range from enhancing efforts to recognize symptoms to
    compassionately communicating to individuals and their caregivers. They
    can then guide U.S. health-care practitioners in the evaluation of
    individuals for memory, thinking, communication and personality
    changes, and symptoms of cognitive impairment, Alzheimer's or another
    dementia. There are several benefits of early and accurate diagnosis
    including participation in clinical trials which allows individuals to
    enroll in clinical trials that advance research and may provide medical
    benefits.

        The Alzheimer's Association looks forward to working with physician
    groups and medical societies to encourage primary care doctors,
    dementia experts, and nurse practitioners to adopt the new guidelines.
    Risk Reduction
        As the scientific field continues to search for a way to cure,
    treat, or slow the progression of Alzheimer's, it is crucial that we
    also focus on reducing the risk of developing the disease in the first
    place. Researchers are increasingly studying the impact that lifestyle
    behaviors may have on the risk of developing Alzheimer's and other
    dementia. The future of reducing Alzheimer's could be in treating the
    whole person with a combination of drugs and modifiable risk factor
    interventions, as we do now with heart disease.

        The Alzheimer's Association is leading a 2-year clinical trial to
    evaluate whether lifestyle interventions that simultaneously target
    multiple risk factors can protect cognitive function in older adults at
    increased risk for cognitive decline. The U.S. Study to Protect Brain
    Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is
    the first such study to be conducted in a large group of Americans and
    will enroll approximately 2,000 older adults, with a particular focus
    on enrolling under-represented populations. The study will evaluate the
    effects of lifestyle interventions, like physical exercise, a healthier
    diet, cognitive and social stimulation, and self-management of heart
    and vascular health, on changes in cognitive function. Vascular and
    metabolic health, physical function, mood, and quality of life will
    also be assessed, and we look forward to sharing the study results in
    2023. Leveraging the Alzheimer's Association investment in U.S.
    POINTER, NIH funding has enabled several important ancillary studies to
    look deeper into the science of the main study. There is a neuroimaging
    ancillary study, which is the first large-scale investigation of how
    lifestyle interventions affect biological changes in the brain
    associated with Alzheimer's and dementia. There is a sleep ancillary
    study to examine whether changes in sleep predict changes in overall
    cognitive function or in specific areas, such as memory. And
    researchers from the Alzheimer's Gut Microbiome Project will examine
    the effects of dietary interventions on microbiome composition and
    function in samples collected from three clinical trials, including
    U.S. POINTER, to understand how variations in the gut microbiome relate
    to cognitive decline and other Alzheimer's-relevant outcomes.

        We are already seeing promising advances in risk reduction
    research. Last year, the Journal of the American Medical Association
    (JAMA) published the groundbreaking results of the SPRINT MIND study,
    the first randomized clinical trial to demonstrate that intensive
    medical treatment to reduce blood pressure can significantly reduce
    risk of mild cognitive impairment (MCI). The study found a
    statistically significant 19-percent reduction in risk of MCI, which is
    important because everyone that develops dementia passes through MCI.
    Preventing new cases of MCI therefore prevents new cases of dementia.
    NIH just announced additional funding to build upon this initial
    finding and further explore the effects of lowering systolic blood
    pressure.

        It is crucial that significant research findings like SPRINT MIND
    are translated into effective public health interventions across the
    country. In 2018, Congress passed the BOLD Infrastructure for
    Alzheimer's Act (Pub. L. 115-406), which would do just that, by
    investing in a robust Alzheimer's public health infrastructure across
    the country. This infrastructure includes Alzheimer's and Related
    Dementias Public Health Centers of Excellence and funding to State,
    local, and tribal public health departments. Congress appropriated $10
    million for the first year of BOLD's implementation in FY 2020, which
    allowed the Centers for Disease Control and Prevention (CDC) to award
    funding to three Public Health Centers of Excellence and 16 public
    health departments across the country this fall. Importantly, one of
    those Centers of Excellence is focused entirely on risk reduction, and
    the Alzheimer's Association is grateful for the opportunity to lead
    this center. While this is a meaningful step forward, CDC must receive
    the full $20 million authorized for BOLD's second year of
    implementation in FY 2021 to ensure the full and necessary impact that
    Congress intended.
                       federal policies for breakthroughs
    Care Planning
        One barrier to the increasing availability of therapeutics in the
    future is the under-diagnosing of Alzheimer's and other dementia. When
    diagnoses are made, they are too often undisclosed by clinicians.
    Without detection and diagnosis, people living with dementia cannot get
    the help they need and may not be able to access therapeutics in a
    timely manner when available. Education of clinicians and individuals
    features prominently in the National Plan to Address Alzheimer's
    Disease.

        Since January 1, 2017, Medicare has reimbursed physicians and other
    health-care professionals for providing comprehensive care planning to
    individuals with cognitive impairment--a critical step in improving the
    quality of care and quality of life for those with Alzheimer's and
    their caregivers. A care planning visit includes an evaluation of
    cognition and function, measuring neuropsychiatric symptoms, a safety
    evaluation, identifying and assessing a primary caregiver, development
    of advance care directives, and referrals to community services.

        The bottom line is that care planning helps ensure those with
    Alzheimer's get on the right care path. Analyses show dementia-specific
    care planning can lead to fewer hospitalizations, fewer emergency room
    visits, and better medication management. It allows diagnosed
    individuals and their caregivers to access medical and non-
    medical treatments, clinical trials, and support services available in
    the community. Alzheimer's and related dementia also complicate the
    management of other chronic conditions, so care planning is key to
    better care coordination and management of comorbid conditions. The
    availability of the care planning code, CPT code 99483, is an
    important step in that direction.

        The Alzheimer's Association and AIM contracted with the Health Care
    Cost Institute to analyze the use of the care planning benefit among
    Medicare fee-for-service (FFS) beneficiaries and among those in some
    Medicare Advantage (MA) plans. Unfortunately, the results illustrate
    that very few Medicare beneficiaries received care planning in 2017,
    the first year it was available. Specifically:

            18,669 FFS Medicare beneficiaries received care planning, a
    rate of 55.6 per 100,000 beneficiaries.
            2,857 individuals in the Medicare Advantage plans that were
    analyzed received the services, a rate of 39.4 per 100,000
    beneficiaries.
            In seven States and Washington, DC, not a single FFS Medicare
    beneficiary received care planning services.

        In short, fewer than 1 percent of those living with Alzheimer's and
    other dementia received care planning in 2017.

        For the benefits of care planning to reach more Americans affected
    by Alzheimer's, more clinicians must use the care planning benefit.
    Introduced by Senator Stabenow, the bipartisan Improving HOPE for
    Alzheimer's Act (S. 880/H.R. 1873), would help achieve that goal by
    requiring the Department of Health and Human Services to (1) educate
    clinicians on the existence and importance of Medicare's care planning
    benefit; and (2) report to Congress on the barriers to individuals
    receiving care planning services and how to increase their use. This
    bill has already garnered significant bipartisan support in both
    chambers.

        Robust care planning is the first step to learning about long-term
    care options and selecting the preferred, most appropriate services for
    persons with dementia, families, and caregivers. Because persons living
    with Alzheimer's and other dementia often use a variety of supports
    over the course of the disease and because many--if not most--people
    need help coordinating those services, a care plan can help these
    individuals sort through options and choose the long-term services and
    supports that can contribute the most to the quality of their life. The
    Alzheimer's Association and AIM urge Congress to pass this critical,
    bipartisan legislation which garnered support from over half of
    Congress in its 20 months since introduction, to support individuals
    living with Alzheimer's and other dementia, and their families, while
    they await treatment options.
          improvements to health-care programs for care coordination,
                            diagnosis, and treatment
    Alternative Payment Model
        In a recent letter from Chairman Toomey and Ranking Member Stabenow
    to Department of Health and Human Services Secretary Alex Azar,
    recommendations were offered on how to strengthen care and services for
    persons living with dementia as well as foster innovation in
    Alzheimer's and dementia research. We support the recommendation to the
    Center for Medicare and Medicaid Innovation (CMMI) to create and test
    alternative payment and coordinated care models targeted toward
    Medicare and/or Medicaid beneficiaries with Alzheimer's and other
    dementia.

        A person with dementia is 4.4 times more likely to have six or more
    other chronic conditions as someone without dementia. Managing these
    chronic conditions is impeded by an individual's cognitive impairment.
    As a consequence, health-care utilization is significantly higher among
    seniors with dementia than among seniors without dementia. The annual
    hospitalization rate is twice as high; the use of skilled nursing
    facilities is nearly four times higher; and hospital/skilled nursing
    facility stays are nearly four times longer. In addition, on average, a
    senior with dementia will visit the emergency room more than once each
    year.

        Many of these costs are simply unnecessary and could be avoided if
    care was properly managed including better coordination of care,
    seamless navigation across the multitude of providers, and timely
    access to care and interventions. There are proven ways to improve the
    quality of care and quality of life--and reduce Medicare spending--if
    the payment barriers standing in the way are broken down. Much of the
    discussion surrounding Alzheimer's disease has focused, importantly, on
    the need for biomedical research to find means to prevent it and
    treatments. It is important to not forget that millions of people
    living with Alzheimer's and other dementia need better care.
                                   conclusion
        It is imperative that Congress and the private sector continue to
    invest in research as we work--together--toward the primary research
    goal to effectively treat and prevent Alzheimer's by 2025. In the
    absence of a treatment that would change the underlying course of the
    disease, we must do all we can to ensure the best quality of care and
    quality of life for those living with Alzheimer's and the people who
    care for them. We look forward to working with the committee to advance
    bipartisan solutions that will have a meaningful impact on people
    living with Alzheimer's and other dementia, including passage of the
    Improving HOPE for Alzheimer's Act. Thank you for your continued
    leadership on investment in NIH funding for Alzheimer's disease and
    other dementia, and improving care, supports, and services for those
    living with Alzheimer's and their caregivers, and we appreciate the
    opportunity to be a resource to the committee.

                                     ______

          Questions Submitted for the Record to Maria Carrillo, Ph.D.
                  Questions Submitted by Hon. Debbie Stabenow
        Question. We know that patients with dementia have been
    particularly suffering during the pandemic due to social isolation and
    the tragically rampant spread of the virus through many long-term care
    facilities.

        Could you discuss how you see the pandemic affecting dementia and
    Alzheimer's patients and caregivers long-term, and how caregivers are
    likely to be impacted?

        Answer. Over 136,000 residents and employees of nursing homes and
    long-term care facilities have died from COVID-19 representing 36
    percent of the total death toll in the United States. These communities
    are on the front lines of the COVID-19 crisis, where 48 percent of
    nursing home residents are living with dementia, and 42 percent of
    residents in residential care facilities have Alzheimer's or another
    dementia. Residents with dementia are particularly susceptible to
    COVID-19 due to their typical age, their significantly increased
    likelihood of coexisting chronic conditions, and the community nature
    of long-term care settings. Across the country these facilities, their
    staff, and their residents are experiencing a crisis due to a lack of
    transparency, an inability to access the necessary testing, inaccurate
    reporting, and more. The Alzheimer's Association and ATM released
    policy recommendations aimed at improving the State and Federal
    response to COVID-19 in long-term care settings. We continue to
    advocate for dedicated funding for daily, rapid-response testing in
    these settings; immediate and accurate reporting; adequate personal
    protective equipment; surge activation like strike teams when needed;
    and televisitation to combat the devastating effects of social
    isolation. The Association has also released COVID-19 Tips for Dementia
    Caregivers to help the 16 million people across the country caring for
    a loved one with Alzheimer's navigate the stress, risks, and additional
    safety precautions needed during the pandemic.

        Question. Are there specific questions related to the pandemic that
    should be researched to better understand how the virus may have
    affected dementia and Alzheimer's patients now and in the future?

        Answer. There is a clear connection between COVID-19 and brain
    dysfunction. Many people have reported loss of smell and taste and
    ``brain fog.'' The damage done by the pandemic will not be limited to
    the acute effects, but will have long-term health consequences that may
    impact many individuals' quality of life and independence. We need to
    better understand the potential damaging effects of SARS-CoV-2 on the
    brain, memory, and behavior. The Alzheimer's Association and
    representatives from more than 30 countries have formed an
    international consortium to study the short and long-term consequences
    of COVID-19 on the brain and nervous system in people at different
    ages, and from different genetic backgrounds. This includes the
    underlying biology that may contribute to higher risk of Alzheimer's
    and other dementia, as well as how COVID-19 may increase the severity,
    pace, and progression of diseases such as Alzheimer's, and psychiatric
    diseases including depression.

        Question. You discussed the need for care planning and the
    importance of Medicare coverage of the service. As I mentioned earlier,
    my Improving HOPE for Alzheimer's Act would require CMS to create and
    implement an education outreach campaign to ensure providers are not
    only aware of the code, but also know how to use it.

        How will the increased use of the care planning code reduce costs
    to Medicare?

        Answer. Senator Stabenow, thank you for your work on the Improving
    HOPE for Alzheimer's Act and ensuring its inclusion in the Consolidated
    Appropriations Act of 2021. The Alzheimer's Association and AIM greatly
    appreciate your continued leadership on issues important to people
    living Alzheimer's and other dementia, and their families.

        For individuals living with Alzheimer's and their caregivers, care
    planning is essential to learning about medical and non-medical
    treatments, clinical trials, and support services available in their
    communities. Alzheimer's and related dementias complicate the
    management of chronic conditions. Access to these services help to
    manage these other conditions and result in a higher quality of life.
    Analyses show getting on the right care path reduces costs to Medicare
    as a result of fewer emergency department visits, fewer
    hospitalizations, and better medication management.

                                     ______

        Prepared Statement of Nikolay Dokholyan, Ph.D., M.S., G. Thomas
     Passananti Professor and Vice Chair for Research, Pennsylvania State
                              College of Medicine
        Thank you, Senators Toomey and Stabenow, for your invitation to
    talk to the Senate Committee on Finance Subcommittee on Health Care
    about the emerging crisis in health care due to Alzheimer's disease. I
    am a scientist whose research is focused on fundamental and
    translational research in neurodegenerative diseases at the Penn State
    University College of Medicine. I have studied neurodegenerative
    disorders for over 20 years, focusing on the fundamental processes that
    lead to the pathological behavior of proteins in human diseases.
    Besides a scientific desire to understand the processes leading to
    neuronal degeneration, like many Americans, I have family members who
    have suffered from Alzheimer's disease, so I know well the emotional as
    well as financial toll it takes on families.

        The burden that the lack of effective therapies and accessible
    diagnostics exerts on public health-care programs like Medicare and
    Medicaid. This includes the fiscal burden stemming from the high costs
    of care for Alzheimer's patients, as well as the unstoppable erosion of
    beneficiaries' health as a result of the disease.

        Alzheimer's disease is a progressive, irreversible, and
    degenerative brain disease. Patients with Alzheimer's disease suffer a
    range of symptoms including memory loss, dementia, confusion,
    aggression, and, especially at the later stages, require significant
    attention from caregivers. Currently, close to 8 million Americans are
    living with diagnosed Alzheimer's disease;\1\ this number is likely a
    significant underestimate due to the lack of early diagnostic tools or
    access to healthcare,\2\ causing many individuals in the early stages
    of disease to remain undiagnosed. Currently, one in 10 people older
    than 65 suffer from Alzheimer's disease,\1\ and one in three adults
    will be diagnosed with the disease by age 85. Women are almost twice as
    likely as men to develop Alzheimer's disease, even after accounting for
    their longer lifespan.\3\, \4\

        Among many genetic and epigenetic risk factors, age is perhaps the
    most critical one. As the U.S. population ages, the number of Americans
    with Alzheimer's disease is projected to double1 by 2050. Today, we
    diagnose a new case roughly every minute; by 2050, we will be
    diagnosing a new case every 30 seconds. Alzheimer's disease is the
    sixth leading cause of death, and the fifth leading cause among adults
    of 65 years or older,\3\ meaning that roughly one in three American
    seniors dies from the disease. The Alzheimer's disease death toll
    increased a staggering 146 percent from 2000 to 2018, while the number
    of deaths attributed to stroke and heart disease, the current leading
    cause of death, decreased roughly 10 percent during this time,
    indicating that Alzheimer's disease in increasing importance as a
    public health issue. Among the top 10 leading causes of death,
    Alzheimer's disease is the only one that cannot be prevented, cured, or
    have its disease progression slowed.\3\, \5\ These numbers,
    however, represent only our best knowledge, and do not accurately
    depict the real penetration of the disease in society. Due to the
    complexity of Alzheimer's disease and its manifestations, as well as
    gaps in scientific knowledge, the illness is often not diagnosed and
    attributed correctly, and so the burden in the population is likely
    higher than it is currently reported.

        Due to the duration of the illness, disease complications, and
    required caregiver attention, the national cost of care for Alzheimer's
    patients and related dementias is a staggering $300 billion, not
    including the over $240 billion cost of unpaid labor from caregivers,
    family, and friends.\3\ These numbers make Alzheimer's disease the most
    expensive disease in the USA. Worldwide, the annual cost of Alzheimer's
    disease exceeded $800 billion in 2015.\6\ The projected costs of
    Alzheimer's disease by 2040 may exceed $500 billion,\7\ and by 2050
    will top $1.1 trillion in the United States alone. A significant
    fraction of the financial burden of the disease falls on the State and
    Federal Governments through the Medicare and Medicaid programs. In
    2020, these programs will cover over $200 billion of expenses
    associated with Alzheimer's disease. The total cost of health care and
    long-term care payments for Alzheimer's patients were at least three
    times that for beneficiaries without Alzheimer's disease. Medicaid
    expenses covering nursing homes and long-term care services are 23
    times higher for Alzheimer's disease patients compared to other
    beneficiaries. Medicare and Medicaid cover close to 70 percent of
    Alzheimer's disease patients' expenses, with the remaining 30 percent
    being uncompensated, private insurance, and out-of-pocket expenses.
    Medicare expenses are projected to grow 400 percent to $589 billion by
    2050, while out-of-pocket expenses will increase 350 percent to $198
    billion. The cumulative costs between 2015 and 2050 are estimated to be
    $20.5 trillion. This projected financial burden is prohibitive and
    demands radical reassessment and prioritization of strategies to
    mitigate Alzheimer's disease.
                 the current state of the alzheimer's disease
                     therapeutics and diagnostic pipelines
        The four principal modalities of health care are diagnostics,
    prognostics, therapeutics, and care (preventative, curative, and
    palliative). All of these modalities contribute to the well-being of
    patients and are aimed at maximizing human health and quality of life.
    Among these modalities, curative therapeutics would have the most
    profound impact on eliminating the financial burden associated with the
    disease, as well as the quality of life of Alzheimer's disease patients
    and their families. The principal challenge in identifying curative
    therapeutics is the current gap in scientific knowledge of the early
    molecular events leading to pathological disease processes, which can
    begin up to 20 years before disease onset. Curative therapeutics
    targeting disease mechanisms, as opposed to palliative therapeutics
    that treat symptoms, strongly depend on an understanding of the
    mechanisms of disease etiology, which is currently sparse. One of the
    hallmarks of Alzheimer's disease is the accumulation of aberrant
    protein deposits in patients' brains. These deposits contain protein
    fragments called amyloid-beta peptide or tau protein. The observation
    of these aggregated proteins has become the central premise for the
    amyloid cascade hypothesis:\8\ that the aggregation process results in
    a toxic gain of function of these proteins, ultimately resulting in
    neuronal death. However, despite decades of research, we have not yet
    established the nature of this link between aggregation and toxicity,
    nor whether protein aggregation is indeed a driver of neuronal death or
    simply a consequence of some unknown underlying processes.
    Nevertheless, the amyloid cascade hypothesis has been the basis for the
    Alzheimer's disease drug pipeline: the majority of drugs that have been
    developed or are currently in clinical trials target either amyloid-
    beta production, promote peptide clearance, inhibit aggregation, or
    promote neuronal resistance to aggregation. Some drugs target tau
    aggregates. However, no significant successes have been reported based
    on the strategies associated with the amyloid cascade hypothesis. Many
    expensive and long clinical trials have been halted at the last
    stages:\5\, \9\, \10\ verubecestat,\11\
    semagacestat,\12\ bapineuzumab,\13\ and solanezumab.\14\ The failed
    drugs succeed in performing their intended functions (e.g., inhibiting
    BACE enzyme in case of verubecestat),\15\ but these functions did not
    translate to the desired clinical outcomes as expected. For example,
    ``verubecestat did not reduce cognitive or functional decline in
    patients with mild-to-moderate Alzheimer's disease and was associated
    with treatment-
    related adverse events.''\16\ In fact, ``no significant new drug for
    Alzheimer's has been approved in the past 14 years, despite massively
    expensive trials aimed at tackling the disease. The pipeline has been
    littered with big failures, which have come in a steady drumbeat of
    defeat and discouragement.''\11\ No preventative therapeutics exist.
    Although a number of palliative therapeutics are either in current
    clinical use or in trials, they ameliorate symptoms but do not
    significantly alter the course of disease. Device-driven interventions
    such as transcranial electromagnetic treatment (TEMT),\17\ transcranial
    direct current stimulation (tDCS),\18\ and photobiomodulation (PBM)
    \19\ are currently being tested for palliative care.

        Presently, there is no definitive clinical diagnostic test for
    Alzheimer's disease. Circumstantial evidence, such as family history,
    interaction with family members and friends, and a battery of cognitive
    tests suggest whether a patient exhibits signs of dementia. Alzheimer's
    disease is the prevalent cause of dementia in older adults, accounting
    for 60-80 percent of cases. In some cases, positron emission tomography
    (PET), magnetic resonance imaging (MRI), and lumbar puncture aid in
    confirming or ruling out Alzheimer's disease in patients with dementia.
    Definitive diagnosis requires histopathologic examination, which is
    necessarily performed only upon autopsy. Diagnosis is particularly
    challenging because the disease may take 20 years to manifest. By the
    time the diagnosis is made, pathology has already significantly and
    irreversibly altered the brain.

        No prognostic models exist for Alzheimer's disease. Genetic
    markers, most notably the presence of one or two e4 variants of
    apolipoprotein E,\20\, \21\ can suggest a higher likelihood
    that a person will develop Alzheimer's disease. However, the presence
    of these genetic risk markers cannot predict with any certainty the
    time frame for disease manifestation, nor whether the carrier will even
    develop the disease at all. Genetic information therefore offers
    potential but not definitive knowledge.
       gaps in data or understanding of the disease that are preventing
                     therapeutic and diagnostic development
        Alzheimer's disease has a complex etiology. Processes that lead to
    neurodegeneration arise at the molecular level and consequently result
    in cellular death, but physiological disease onset and consequent
    cognitive manifestation occurs only after massive and irreversible
    neuronal loss (Figure 1). As a result, neurodegenerative diseases are
    age-related and take from years to decades to manifest, by which time
    the only treatment available to mitigate the disease is alleviation of
    noxious symptoms, including palliative care. The paramount challenge of
    developing treatments for neurodegenerative diseases lies in
    identifying the early pathological events that would eventually result
    in cell death, and targeting those events to rescue the afflicted
    neurons.

        Molecular etiologies of neurodegenerative diseases are among the
    greatest mysteries and challenges in medicine. One common denominator
    in all neurodegenerative disease is the presence of pathological
    protein deposits that occur in distinct and specific regions of the
    brain and/or spinal cord. This common denominator has become the
    central premise for the amyloid cascade hypothesis.\8\ The presence of
    amyloid-beta plaques and tau neurofibrillary tangles are the
    pathophysiological hallmarks of Alzheimer's disease, and for decades
    this association has fueled research focusing on the amyloid cascade
    hypothesis.

    [GRAPHIC] [TIFF OMITTED] T2162.001

        .epsThe uncertainty of whether the disease will manifest in a
    particular individual poses a challenge in identifying the abnormal
    events leading to neuron death. Identifying early pathological events
    is also challenging due to current technological limitations, such as a
    lack of precise and accurate methods for non-invasive monitoring of
    pathological molecular processes. A second significant limitation is
    our lack of disease model systems that faithfully replicate the
    pathology seen in human disease. The current state-of-the-art animal
    models, which are engineered to represent human disease in experiments,
    exhibit significant differences in the aging process between
    experimental animals and humans, as well as artifacts and biases
    brought about by introducing human genes into animals. These studies,
    therefore, require extensive validation from orthogonal studies using
    different methods to test the same question. Hence, we need to not only
    challenge the methods of interrogating the complexities of
    neurodegenerative diseases, but even how we design methods to approach
    these complexities.

        Alzheimer's disease and other neurodegenerative diseases like
    Parkinson's disease and amyotrophic lateral sclerosis share many
    commonalities, such as protein aggregation, neuronal death, and the age
    of onset is typically in the sixties. Such similarities point towards
    fundamental processes common to these diseases, which are still
    unknown. Yet, such similarities suggest that understanding one
    neurodegenerative disease etiology will likely have a profound impact
    on understanding of other ones. As of now, neurodegenerative diseases
    do not have therapies that would even slow down the progression, unlike
    other diseases such as cancer and heart disease. No biomarkers that
    detect early events in the disease are established. Hence, the field of
    neurodegeneration needs new and disruptive thoughts and approaches to
    have a hope of altering their courses.
         challenges to private-sector engagement in the development of
        therapeutics and diagnostics, and potential solutions to these
                                   challenges
        The for-profit private sector is driven by deliverables, and, thus,
    balances knowledge of drug targets against the risks associated with
    them. Although Alzheimer's disease is a potentially lucrative area for
    the pharmaceutical and biotechnological industries, the cost associated
    with clinical trials and their length is a significant deterrent. The
    pharmaceutical industry is under significant pressure to create novel
    and innovative solutions and, thus, has one of the highest research and
    development expenditures among all industries. Despite remarkable
    spending on research in the pursuit of such innovation, pharmaceutical
    companies typically focus on already established drug targets. These
    drug targets are a reflection of our fundamental understanding of
    disease pathological processes, an understanding that is typically
    established in academia. Currently, we do not have a validated model of
    these processes in Alzheimer's disease. Fundamental studies of basic
    science are prohibitively expensive to industry, which relies on
    academia to develop such models. Several drugs currently in the
    clinical trials pipeline, as well as those already approved and those
    that failed clinical trials, have been developed based on the amyloid
    cascade hypothesis and are aimed at reducing the amyloid-beta load in
    patients' brains. Some scientists attribute the failure of these drugs
    to the late timing of intervention in trials, when disease is already
    advanced to irreversible neuron death and consequent cognitive decline.
    However, evidence stemming from other fields suggest that this
    hypothesis needs to be revisited. For example, the research in my
    laboratory on amyotrophic lateral sclerosis suggests that very early
    events in molecular life are responsible for neuronal toxicity,\22\
    while the large protein deposits actually serve as protective buffers
    against those events.\23\ Deeper integration of the private sector with
    academia may significantly reduce the inertia in the drug pipeline and
    potentially offer new ideas to tackle neurodegeneration. Additionally,
    further outsourcing basic scientific research to academia will
    significantly reduce the financial burden associated with therapeutic
    development.

        Charitable foundations are typically driven by donors' immediate
    need to help their loved ones. Their mission is mostly centered around
    research that promotes drug discovery and other short-term goals, but
    the resources are significantly more limited than those available to
    for-profit organizations. Nevertheless, these organizations have been
    instrumental in offering support to academia, thus providing a critical
    springboard for risky and innovative research. In addition,
    organizations such as the Alzheimer's Association foster scientific
    advances not only through research but also through education and
    shared resources.

        The failure to discover curative therapeutics for Alzheimer's
    disease may be a consequence of the exclusive focus on specific targets
    without a validated model of the molecular underpinnings of disease.
    Given the high rate of failure thus far, such a model is likely to come
    from innovative research that disrupts common thought about the
    disease. Hence, stimulating such research by the private sector will
    likely have an immense impact on our progress toward a cure for
    Alzheimer's disease.
      other barriers throughout the research and development process and
      approval process for alzheimer's disease and potential solutions to
                                 these barriers
        Federal grant programs, specifically those sponsored by the
    National Institutes of Health, offer support for both fundamental and
    translational biomedical research. At the NIH, scientific merit reviews
    are performed by scientists, and, therefore, offer a broad and fair
    coverage of research directions. These grant programs are highly
    competitive, and thus proposals that offer something radically
    different and risky (``high risk, high reward'') tend to fair worse
    than risk-averse proposals that continue established lines of research.
    While the NIH has provided venues for high-risk high-return projects,
    they remain extremely competitive, especially for younger scientists
    and those with new ideas who come from outside of a traditional
    neuroscience background.

        Protein aggregation is a hallmark of neurodegenerative diseases,
    including Alzheimer's disease. The mechanisms of protein aggregation
    are understood from a biophysical perspective, but how this molecular
    knowledge relates to physiology remains unknown. Thus, translational
    science programs aimed at marrying disparate scientific fields with
    clinical research are critical to establish a working model of disease.
    The success of translational science relies on attracting scientists
    with backgrounds in diverse fields to build inter-disciplinary
    programs. In addition, attracting industrial partners to these inter-
    disciplinary consortiums will facilitate their progress.

        The dominant cost associated with caring for Alzheimer's disease
    patients stems from the extensive care required in later stages of the
    disease. Reducing the cost of care is mostly an untapped direction in
    mitigating the growing cost of the disease in the United States. Recent
    scientific and engineering innovations, especially in machine learning
    and artificial intelligence, wireless solutions, and miniature devices,
    may offer new and unparalleled means of caring for patients, especially
    in the advanced stages of the disease. For example, wearable devices
    with geofencing abilities may allow automated remote monitoring of a
    patient's health state, while location services may significantly
    reduce the risk of a patient with dementia wandering from home, thus
    allowing those with Alzheimer's disease to remain at home and out of
    care homes for longer. Facilitating such innovations through Federal
    and private sector programs will have a major impact on improving the
    quality of care and reduce financial burden on both government programs
    and on individuals.

    End Notes

    \1\ Hebert, L.E., Weuve, J., Scherr, P.A. and Evans, D.A. Alzheimer
                disease in the United States (2010-2050) estimated using
                the 2010 census. Neurology 80, 1778 LP-1783 (2013).

    \2\ Thorpe, J.M., Van Houtven, C.H., Sleath, B.L. and Thorpe, C.T.
                Rural-Urban Differences in Preventable Hospitalizations
                Among Community-Dwelling Veterans With Dementia. J. Rural
                Heal. 26, 146-155 (2010).

    \3\ Association, A. 2019 Alzheimer's disease facts and figures.
                Alzheimer's Dement. 15, 321-387 (2019).

    \4\ Podcasy, J.L. and Epperson, C.N. Considering sex and gender in
                Alzheimer's disease and other dementias. Dialogues Clin.
                Neurosci. 18, 437-446 (2016).

    \5\ Cummings, J.L., Morstorf, T. and Zhong, K. Alzheimer's disease
                drug-development pipeline: Few candidates, frequent
                failures. Alzheimer's Res. Ther. 6, 1-7 (2014).

    \6\ Prince, M. et al. Alzheimer's Disease International: World
                Alzheimer's Report 2015: The Global Impact of Dementia: An
                Analysis of Prevalence, Incidence, Cost and Trends. 2015.
                Alzheimer's Dis. Int. London (2019).

    \7\ Hurd, M.D., Martorell, P., Delavande, A., Mullen, K.J. and Langa,
                K.M. Monetary costs of dementia in the United States. N.
                Engl. J. Med. 368, 1326-1334 (2013).

    \8\ Hardy, J.A. and Higgins, G.A. Alzheimer's disease: The amyloid
                cascade hypothesis. Science (80-. ), 256, 184 LP-185
                (1992).

    \9\ Anderson, R.M., Hadjichrysanthou, C., Evans, S. and Wong, M.M. Why
                do so many clinical trials of therapies for Alzheimer's
                disease fail? Lancet 390, 2327-2329 (2017).

    \10\ Gauthier, S. et al. Why has therapy development for dementia
                failed in the last two decades? Alzheimer's Dement. 12, 60-
                64 (2016).

    \11\ Carroll, J. Another Alzheimer's drug flops in pivotal clinical
                trial. Sci. News. Available online http//www.Sci.org/news/
                2017/02/anotheralzheimers-drug-flops-pivotal-clinical-trial
                (accessed January 31, 2018) (2017).

    \12\ Doody, R.S. et al. A phase 3 trial of semagacestat for treatment
                of Alzheimer's disease. N. Engl. J. Med. 369, 341-350
                (2013).

    \13\ Vandenberghe, R. et al. Bapineuzumab for mild to moderate
                Alzheimer's disease in two global, randomized, phase 3
                trials. Alzheimer's Res. Ther. 8, 18 (2016).

    \14\ The, L. N. Solanezumab: Too late in mild Alzheimer's disease?
                Lancet. Neurol. 16, 97 (2017).

    \15\ Forman, M. et al. O1-06-05: The novel BACE inhibitor MK-8931
                dramatically lowers CSF beta-amyloid in patients with mild-
                to-moderate Alzheimer's disease. Alzheimer's Dement. 9,
                P139-P139 (2013).

    \16\ Egan, M.F. et al. Randomized trial of verubecestat for mild-to-
                moderate Alzheimer's disease. N. Engl. J. Med. 378, 1691-
                1703 (2018).

    \17\ Clinicaltrials.gov. Transcranial Electromagnetic Treatment (TEMT)
                Against Alzheimer's Disease, 2020, www.clinicaltrials.gov/
                ct2/show/NCT04271163?
                term=NCT04271163.

    \18\ Clinicaltrials.gov. Therapeutic Role of Transcranial DCS in
                Alzheimer, 2020, www.clinicaltrials.gov/ct2/show/
                NCT03313518?term=NCT03313518.

    \19\ Clinicaltrials.gov. Photobiomodulation for Improving Brain
                Function in Dementia (PBM Dementia), 2020,
                www.clinicaltrials.gov/ct2/show/NCT03160027?
                term=NCT03160027.

    \20\ Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele
                and the risk of Alzheimer's disease in late onset families.
                Science (80-. ), 261, 921-923 (1993).

    \21\ Strittmatter, W.J. et al. Apolipoprotein E: high-avidity binding
                to beta-amyloid and increased frequency of type 4 allele in
                late-onset familial Alzheimer's disease. Proc. Natl. Acad.
                Sci. 90, 1977-1981 (1993).

    \22\ Proctor, E.A. et al. Nonnative SOD1 trimer is toxic to motor
                neurons in a model of amyotrophic lateral sclerosis. Proc.
                Natl. Acad. Sci. U.S.A. 113, 614-619 (2016).

    \23\ Zhu, C., Beck, M.V, Griffith, J.D., Deshmukh, M. and Dokholyan,
                N.V. Large SOD1 aggregates, unlike trimeric SOD1, do not
                impact cell viability in a model of amyotrophic lateral
                sclerosis. Proc. Natl. Acad. Sci. 115, 4661 LP-4665 (2018).

                                     ______

      Questions Submitted for the Record to Nikolay Dokholyan, Ph.D., M.S.
                   Questions Submitted by Hon. Chuck Grassley
                      alzheimer's screening and diagnosis
        Question. You testified that Alzheimer's disease is under-diagnosed
    and underreported. With other diseases, particularly cancer, we've seen
    the impact that an early diagnosis can make on a patient's life. Other
    than stigma or lack of diagnostic testing resources, what are some of
    the typical reasons for a delayed Alzheimer's diagnosis? Is there more
    that we could be doing to encourage earlier screening for Alzheimer's
    disease?

        Answer. Currently, Alzheimer's disease diagnosis relies on reports
    of memory loss and early stages of dementia. More sophisticated and
    expensive approaches rely on positron emission tomography (PET) imaging
    that measures the levels of amyloid beta peptide in the brain (one of
    the key markers of Alzheimer's disease) to confirm Alzheimer's disease
    in patients with dementia. More recently, a significantly less
    expensive blood-based biomarker, also based on amyloid beta peptide
    load, has been developed by Dr. Randall Bateman at the Washington
    University School of Medicine. This new development will revolutionize
    our ability to screen patients with early signs of dementia.

        Even these new advanced methods for diagnosis of Alzheimer's
    disease rely on the outcomes of processes that have been active in
    patients' brains for years. We still do not know how early these
    processes start, but by the time diagnosis is possible, even with new
    advanced techniques, sufficient irreversible brain damage is present to
    result in cognitive decline or even full-blown dementia. The catch-22
    here is that in order for a patient to be tested, s/he needs to exhibit
    cognitive decline, which is the result of the irreversible brain
    damage. Resources to perform early screening of patients with mild
    cognitive decline will certainly help inform patients of lifestyle
    choices to mitigate the condition. However, we desperately need to
    examine early molecular events that result in neuronal death.

        Question. It's been reported that researchers have found specific
    markers in the blood that could detect changes in the brain 20 years
    before Alzheimer's symptoms occur. Are you aware of this research, and
    if so, what more can you tell us about how close we are to having a
    widely available blood test for Alzheimer's? What other challenges
    remain?

        Answer. Several labs, notably Dr. Randall Bateman's laboratory,
    have been pushing the boundaries of Alzheimer's disease diagnostics via
    blood-based biomarkers, which measure either amyloid beta or tau
    loads--both peptides associated with Alzheimer's disease. These tests
    are highly accurate for Alzheimer's disease pathology (>90 percent),
    but are not stand-alone diagnostic tools yet and they require
    orthogonal confirmation of the disease by a physician confirming
    cognitive impairment. Furthermore, even though they are significantly
    less expensive than PET scans, the expenses associated with such tests
    may still be prohibitive for massive utilization in the clinic, because
    the CLIA approved tests are not yet covered by CMS or insurance.
    Implementation in the clinic and coverage by CMS continue to be major
    challenges.

                                     ______

                     Question Submitted by Hon. John Thune
        Question. I understand that there have been multiple studies to
    explore how artificial intelligence (AI) can help predict Alzheimer's
    in patients. Some of these studies have involved training computers to
    analyze clinical data and scans, and others have utilized handwriting
    and linguistic analysis to predict future diagnoses. What role do you
    see AI playing in the fight to address Alzheimer's and the financial
    effects it has on Medicare and Medicaid?

        Answer. The progress in machine learning, a sub-field of
    mathematics and computer science, has led to significant breakthroughs
    across multiple disciplines, including the biomedical and clinical
    sciences. In Alzheimer's disease, I see three principal domains for
    application of machine learning and artificial intelligence. First,
    machine learning and artificial intelligence may find application in
    identification of early biomarkers of the disease, which would precede
    detectable abundance of amyloid beta peptides, but such a technology
    would strongly depend on our understanding of the biological processes
    associated with the disease. Second, these computational approaches may
    be able to detect early signs of cognitive decline and behavioral
    changes that would predate mild cognitive decline states of Alzheimer's
    patients. Third, machine learning coupled with innovation in
    electronics and wearable devices may help mitigate behavioral changes
    in Alzheimer's disease patients, thereby significantly reducing the
    burden on care providers. These three domains require translational
    science approaches to successfully implement them by connecting
    scientific and engineering knowledge with clinical practice.

                                     ______

                     Question Submitted by Hon. Todd Young
        Question. While CMS has made some minor changes to the provider
    guidance regarding the detecting cognitive impairment requirement of
    the Annual Wellness Visit (AWV), it seems that the AWV continues to be
    a missed opportunity for early detection of cognitive impairment.

        Would the detection of cognitive impairment requirement be enhanced
    by the use of NIA-identified assessment tools or is ``direct
    observation'' an acceptable standard for evaluating cognitive
    impairment in aging populations?

        Answer. While implementation of more comprehensive assessments may
    help with earlier detection of dementia, there may be much more
    innovative and less expensive means to this end for Alzheimer's
    disease, for example, using machine learning and artificial
    intelligence approaches.

                                     ______

                  Prepared Statement of Hon. Chuck Grassley,
                            a U.S. Senator From Iowa
        Alzheimer's is a devastating, irreversible disease that strips
    individuals of their memories and their life. At least 5 million people
    in the United States are living with it today, according to the
    Alzheimer's Association. That number will only increase as our
    population continues to age.

        Alzheimer's also profoundly affects family caregivers. We need to
    do more to respond in more ways to the issues facing the 16 million
    Americans who currently provide unpaid care for people with dementia.
    The brunt of this work is done by family members.

        Through investments in scientific research, we've made some
    advances in detecting and tracking this devastating disease. Congress
    has played a supportive role in this respect, and I expect we'll
    continue to do so, by providing resources for research to find the
    cause and the cure for Alzheimer's. We still have much more work to do
    on this front, however, as we've yet to find a cure or ways to prevent
    Alzheimer's.

        I also am concerned about the exploitation of individuals living
    with Alzheimer's or other forms of dementia. During my tenure as
    Judiciary Committee chairman, I championed bipartisan legislation to
    update and extend the Missing Alzheimer's Patient Alert Program.

        More recently, I joined Senators Collins and Menendez in
    championing a bill requiring the Justice Department to take into
    account people with Alzheimer's disease when creating or compiling
    elder abuse training materials. This measure builds on legislation I
    sponsored in 2017, which required the Justice Department to appoint an
    Elder Justice Coordinator and create training materials to help Federal
    investigators respond to elder abuse cases.

        I thank my colleagues, Senators Toomey and Stabenow, for convening
    this very important hearing of our Health Subcommittee. I also extend a
    warm welcome to each of our witnesses. I look forward to hearing more
    from them about their latest research on Alzheimer's disease and the
    potential for a cure.

                                     ______

     Prepared Statement of Richard C. Mohs, Ph.D., Chief Science Officer,
                     Global Alzheimer's Platform Foundation
        Thank you, Senators Toomey and Stabenow and members of the
    subcommittee, for your support for Alzheimer's research and for the
    opportunity to testify before the Senate Committee on Finance
    Subcommittee on Health Care.

         Today I will address the state of Alzheimer's research, the
    importance of pursuing multiple approaches to treatment, the importance
    of fast and low-cost blood biomarkers and digital cognitive
    assessments, the need for greater diversity in clinical trials, the
    innovative Bio-Hermes study, and recommendations for Congress.

        For the past 40-plus years, both as an academic researcher funded
    by the National Institutes of Health (NIH) and subsequently leading
    drug development teams in the pharmaceutical industry, I have devoted
    much of my scientific career to trying to develop new medicines for
    Alzheimer's disease (AD). We have not been as successful as I would
    like or as successful as patients need. So far only two groups of
    medicines have been approved for use in patients with Alzheimer's
    disease. They are the cholinesterase inhibitors and one NMDA (N-Methyl-
    d-aspartate) antagonist; these medicines provide relatively small
    symptomatic improvements in patients with mild or moderate disease but
    do not prevent the disease or slow its relentless progression.

        Currently, I am the chief science officer for the Global
    Alzheimer's Platform (GAP) Foundation. GAP is a patient-centered non-
    profit organization devoted to accelerating the delivery of innovative
    therapies for neurological disorders by reducing the duration and cost
    of clinical trials. More than 85 clinical research centers across the
    U.S. and Canada are part of the growing GAP Network, known as GAP-Net.
    GAP supports GAP-Net research sites by assisting with study start up
    and recruitment activities, promoting diversity in research studies and
    offering national programs that champion brain health and the citizen
    scientists who make research possible.

        I joined GAP in 2015 after retiring from Eli Lilly and Company;
    prior to joining Lilly in 2002, I was on the faculty of the Mount Sinai
    School of Medicine in New York. Based on my experience both in academic
    research and in the pharmaceutical industry I can offer some
    perspectives on the work that has been done in AD therapeutics,
    barriers to progress and on future initiatives that could speed
    progress that is so urgently needed.

        The first and most significant barrier to progress in developing
    new medicines is that we have not yet clearly identified the key
    biological processes causing AD. As we have learned in recent months
    from experience with COVID-19, once a clear causal agent is identified
    and characterized biologically, the search for preventative measures
    and treatments can proceed rationally through the conduct of highly
    informative basic and clinical research. For a chronic disease such as
    Alzheimer's with multiple risk factors and with complex pathology the
    path to effective treatments is quite uncertain. In the private sector,
    there is a high degree of interest and considerable investment in
    Alzheimer's disease drug development, but it is considered more risky
    than other therapeutic areas where the perceived likelihood of clinical
    and commercial success is seen as higher. This is one reason why we
    haven't seen the number of successful new medicines we have seen in
    oncology, autoimmune diseases, diabetes and other conditions.

        We do know that AD is characterized by the presence of two abnormal
    proteins in brain, amyloid plaques and tau tangles. Many drugs designed
    to slow the accumulation or speed the removal of amyloid plaques have
    been entered into large, time-consuming and very expensive clinical
    trials. Some of these drugs have been shown to have potent biological
    effects on amyloid and it is likely that some clinical benefit may
    follow but much uncertainty remains. Drugs to reduce the spread of the
    abnormal tau protein in brain are currently being tested and their
    clinical efficacy remains uncertain. While these approaches may show
    some efficacy in some patients it is unlikely that either approach will
    be sufficient to prevent most cases of AD or to completely stop disease
    progression. It is imperative that the therapeutic value of targeting
    other factors associated with AD etiology and pathology be tested as
    quickly as possible. As examples, drugs targeting apolipoprotein E
    (APOE), a major risk factor for AD, brain inflammation, mechanisms of
    brain cell death, and neuronal activity should be developed and tested
    as quickly as possible. The GAP Foundation has worked over the past
    several years to develop a network of clinical trial sites using common
    processes for clinical study contracting, Ethical Review, participant
    recruiting and citizen engagement to help clinical sites conduct
    studies quickly and produce reliable, informative data.

        Speeding the delivery of highly informative clinical data on
    promising drug candidates will require renewed effort and collaboration
    of government agencies, pharmaceutical companies, clinical trial sites,
    and, importantly, citizens willing to engage as informed and willing
    participants in clinical trials. Broadly speaking, academic and
    government investigators provide many of the insights into etiology and
    brain pathology that could be targeted with new medicines; commercial
    entities discover and provide the early evaluation of most of the
    viable drug candidates; pharmaceutical companies, clinical trial sites
    and the government funders such as the NIH then work to support the
    collection of clinical data, all of which can then be submitted to Food
    and Drug Administration (FDA) for review.

        Given the complexity of AD we must expect that many clinical
    trials, even those testing the most scientifically promising drug
    candidates, will fail to show efficacy. We should not regard these as
    complete failures, however, since well-designed and executed clinical
    trials of good candidate molecules provide information that is
    essential for planning future drug discovery and development
    activities. By testing a variety of scientifically justified approaches
    in efficient and well executed clinical studies and learning from each
    set of studies, I am very confident that we will develop effective
    medicines for the prevention and treatment of AD. We need to take
    lessons from earlier unsuccessful programs using large, expensive and
    time-
    consuming studies to identify faster and more efficient methods to test
    promising new molecules.

        A second major barrier is the disconnect between the way patients
    with AD are diagnosed in current clinical practice and the way research
    studies identify study participants. Most practicing physicians wait
    and make a diagnosis of AD relatively late, when patients manifest
    clear symptoms and need counseling on how to manage those symptoms. We
    now know that the pathology of AD begins in the brain many years before
    patients develop symptoms such as memory loss and impairment in
    activities of daily living. Biomarkers, particularly PET (positron
    emission tomography) brain scans now enable the detection of amyloid
    and tau pathology well before symptoms of AD are noticeable. Many drugs
    in development are expected to be most effective by intervening when
    pathology is just starting rather than when it has advanced enough to
    cause major impairment. As a result, clinical trial sponsors must
    evaluate many potential study participants with cognitive tests and
    expensive, time-consuming PET scans in order to enroll appropriate
    trial participants; that is, participants with AD pathology but with
    only mild or no symptoms.

        Very recently major advances have been made in the development of
    simple blood-based biomarkers that will speed the identification of
    people with asymptomatic disease both for trials and for early
    diagnosis in clinical practice. The development of blood biomarker
    tests and incentivizing their widespread use in clinical practice is
    very important. They will allow us to make diagnoses earlier and at a
    lower cost. Early diagnoses will allow for scaling up education efforts
    and counseling, so that families can make plans for their loved one to
    have the highest degree of independence possible, ideally in their own
    homes. Early diagnoses also will facilitate the rapid completion of
    clinical studies because we will identify and enroll appropriate
    participants in clinical trials much earlier.

        The GAP foundation is in the process of standing up a platform
    study that will test the efficacy of more than a dozen promising blood
    biomarkers and digital cognitive assessments as prognostic or
    diagnostic indicators for Alzheimer's disease. Known as the Bio-Hermes
    study, it will generate biological samples and digital biomarker data
    from 1000 participants; the study will also enable development of a
    data algorithm to produce next-generation clinical trial enrollment
    solutions. The Bio-Hermes study will include racially and ethnically
    diverse participants in order to assess whether biomarker risk factors
    vary by race and ethnicity.

        Recruiting a diverse group of informed and willing participants for
    an Alzheimer's clinical trial is both extremely important and
    challenging. Despite making up about 30 percent of the US population,
    African American and Latino people usually make up only about 3-8
    percent of clinical trial participants. To help address this issue, GAP
    has committed to recruiting at least 20 percent African American or
    Latino volunteers for the upcoming Bio-Hermes study, and will not close
    recruitment for this trial until we have a group of study participants
    that accurately reflects the community of people living with
    Alzheimer's disease. Our intention is for the Bio-Hermes study to be a
    model for building back a clinical trial infrastructure that is more
    efficient and gets us to a better diagnostics and medicines faster.

        Of course, the Food and Drug Administration (FDA) is an essential
    partner to the pharmaceutical industry and academic researchers when it
    comes to the search for better diagnostics and treatments for
    Alzheimer's disease. We applaud the agency's approach to public
    engagement around their evaluations. We appreciate that the FDA has
    been transparent and energetic in its collaboration with a broad range
    of stakeholders, including patient advocates, researchers and
    pharmaceutical companies. Given the need for greater diversity in
    clinical trials, we hope Congress will use the Prescription Drug User
    Fee Act renewal process to encourage FDA to develop clear guidance on
    minimum standards for diversity in clinical trials.

        We hope that Congress will encourage greater collaboration between
    FDA and the Centers for Medicare and Medicaid Services (CMS) so that
    future reviews regarding efficacy of new diagnostics and medicines and
    consideration of their merits for reimbursement can occur concurrently.
    This would help speed the delivery of innovative diagnostics and
    medicines to patients and clinicians.

        Undoubtedly Alzheimer's Disease has proven to be one of the most
    difficult problems ever to confront biomedical researchers. I look
    forward to discussing how the subcommittee can take steps to speed the
    widespread use of blood biomarkers and digital cognitive assessments,
    increase the speed and diversity of Alzheimer's clinical trials,
    enhance investment in the AD clinical research infrastructure and
    encourage further collaboration between commercial sponsors, academic
    researchers, NIH, FDA, patient stakeholders and CMS.

                                     ______

          Questions Submitted for the Record to Richard C. Mohs, Ph.D.
                     Questions Submitted by Hon. John Thune
        Question. South Dakota has long embraced telehealth, including in
    long-term care settings where residents may experience Alzheimer's. Of
    course, the pandemic has brought telehealth even further to the
    forefront, connecting patients to their doctors from the safety and
    convenience of their own home. What further can policymakers and CMS be
    doing to expand telehealth to assist Alzheimer's patients?

        Answer. Remote clinical visits with physicians or other health-care
    providers can be done effectively using several modalities including
    video conference, telephone, email, and text message. In some regions
    of the U.S., Internet speeds may be slow and prohibit telemedicine
    services but still allow other types of remote assessments and
    treatments. All forms of remote assessment and treatment that have been
    shown to be effective should be reimbursed. Currently some clinical
    services may not be reimbursed if given remotely even though data
    indicate that remote administration is effective.

        I also note that a full diagnostic evaluation of persons with
    cognitive impairment involves expensive, time consuming, and, for some
    patients, intimidating procedures. This barrier makes it difficult to
    diagnose Alzheimer's disease early, particularly in poor communities
    and communities without sophisticated health systems. Blood and digital
    biomarker tests such as those to be evaluated in the Bio-Hermes study
    are simple, cheap and accessible for neighborhood and sophisticated
    health systems alike. Widespread adoption of these tests could help
    people get diagnosed earlier, greatly and equitably increasing the
    patient population available for clinical trials.

        Question. I understand that there have been multiple studies to
    explore how artificial intelligence (AI) can help predict Alzheimer's
    in patients. Some of these studies have involved training computers to
    analyze clinical data and scans, and others have utilized handwriting
    and linguistic analysis to predict future diagnoses. What role do you
    see AI playing in the fight to address Alzheimer's and the financial
    effects it has on Medicare and Medicaid?

        Answer. Annual screenings of the very large number of people at
    risk for Alzheimer's disease will be very costly and cumbersome if done
    entirely by clinicians. Evidence indicates that AI applied to data in
    electronic health records and collected from electronic devices such as
    activity monitors, smart watches, phones and computers could increase
    the number of Alzheimer's disease patients identified and make the
    process less costly. Privacy and consent issues regarding the use of
    individually identified data need to be resolved. Research to determine
    the most effective AI approaches should be encouraged and supported.

                                     ______

                     Questions Submitted by Hon. Todd Young
        Question. While CMS has made some minor changes to the provider
    guidance regarding the detecting cognitive impairment requirement of
    the Annual Wellness Visit (AWV), it seems that the AWV continues to be
    a missed opportunity for early detection of cognitive impairment.

        Would the detection of cognitive impairment requirement be enhanced
    by the use of NIA-identified assessment tools or is ``direct
    observation'' an acceptable standard for evaluating cognitive
    impairment in aging populations?

        Answer. Many different tools, processes, and technologies may be
    useful for detecting cognitive impairment; cognitive tests done in
    person, direct observation by a trained clinician, remote tests, data
    from electronic health records and wearable devices may all assist
    clinicians in identifying persons with cognitive impairment. The NIA-
    identified tests will be useful for clinicians who have the training
    and experience needed to use them properly. I think that the Food and
    Drug Administration (FDA) has the most well-developed process for
    evaluating the usefulness of any new technology or algorithm. The FDA
    can evaluate data on new technologies and approve language that
    accurately informs clinicians about how the technology should be used.
    Their evaluation provides an appropriate context of use for each
    technology.

        Question. CMS allows a variety of providers to conduct an AWV,
    ranging from physicians, PAs, and nurse practitioners to dietitians and
    nutrition professionals.

        Given this provider range, what type of training do these providers
    receive when it comes to detecting cognitive impairment?

        Answer. Clinicians with a variety of different backgrounds can be
    trained to detect cognitive impairment; this can include physicians,
    nurses, psychologists, social workers and others. Specific, supervised
    training on test administration should be required along with
    supervised experience evaluating patients with dementia.

        Question. Given progress made in assessment tools sensitivity to
    detecting cognitive impairment, should the use of an assessment tool
    included in the NIA's toolbox of resources for professionals be
    standard practice at Medicare annual appointments, or is direct
    observation an equal substitute?

        Answer. Both cognitive tests such as those included in the NIA
    toolbox and direct observation can be used to identify patients with
    cognitive impairment. The clinicians using the test or making the
    observation should have supervised training and experience needed to
    interpret the observations. As noted previously, new technologies such
    as those involving AI, wearable devices, and remote assessments can
    also assist in identifying persons with cognitive impairment. An
    approval process for these new technologies can be based on the
    biomarker evaluation process available through the FDA.

        Question. Do you think there is a reasonable argument against CMS
    directing providers to use assessment tools that the NIA already refers
    providers to in other areas?

        Answer. The tools recommended by NIA are reasonable and should be
    used by clinicians with appropriate training and experience. Other
    procedures and tools for identifying patients with cognitive impairment
    can also be useful. As noted above, standards for evaluating new tools
    and technologies are available through FDA. Such evaluations can
    provide clinicians with guidance on how to administer and interpret any
    approved test.

        Question. Do you think CMS has a valid reason to be against
    directing providers to use assessment tools that the NIA already refers
    providers to for use in other Medicare benefits?

        Answer. The NIA-recommended tools are useful and should be used by
    clinicians with appropriate training and experience.

                                     ______

                   Question Submitted by Hon. Debbie Stabenow
        Question. You discussed the need to encourage diversity among trial
    participants as well as ensure early diagnosis to enroll patients in
    clinical trials.

        How would the CHANGE Act and standardizing cognitive assessment
    tools help patients enroll in clinical trials?

        Answer. The CHANGE Act provides for cognitive assessments at the
    Annual Wellness Visit and, for patients with evidence of cognitive
    impairment, encourages referral to clinical trials. If these provisions
    of the CHANGE Act were widely adopted the number of persons with
    suspected cognitive impairment would likely increase substantially and
    the number of patients referred for clinical trials would also
    increase. This would lead to improved care, counseling and patient
    management for patients with cognitive impairment. It would also
    increase the number of patients enrolling in clinical trials and reduce
    the time needed to evaluate potential new medicines and other
    therapies.

                                     ______

                  Prepared Statement of Hon. Debbie Stabenow,
                          a U.S. Senator From Michigan
        Thank you, Mr. Chairman. It is my pleasure to join you in hosting
    this subcommittee hearing, and I know how passionate we both are on
    this issue, and I really appreciate the work that we have been doing
    together on this subcommittee. And I appreciate all of our colleagues
    joining us today.

        Also, thank you to our witnesses for all you are doing and for
    being here--virtually--today as we discuss this incredibly important
    topic.

        There are 5.8 million Americans living with Alzheimer's today, and
    that includes 190,000 people in my home State of Michigan. In just the
    next 30 years, that number is expected to more than double to 14
    million Americans.

        And we know that the pandemic has hit dementia patients especially
    hard, with well over 13,000 excess deaths attributed to Alzheimer's
    since March. Behind these numbers, though, are what's most important,
    and that's grandparents and parents, aunts and uncles, and friends,
    moms and dads, loved ones who have faced this horrific diagnosis and
    the limited treatment options right now.

        Today, we will learn the latest developments on Alzheimer's
    treatments and testing. There's still no drug, as the chairman said, to
    cure Alzheimer's disease or slow its progression--but there is hope.

        I am pleased that the Federal funding for Alzheimer's research is
    five times higher now than it was just 9 years ago. And I agree that we
    need to do much more.

        With this funding, many researchers have been able to make strides
    toward new treatments. I know in my home State, there's tremendous work
    being done. We need to continue to support their groundbreaking work
    and to expand on it.

        We also need better testing, so we can identify the disease early,
    help families plan, and get people enrolled in clinical trials. And
    when we have a treatment, early and affordable testing and diagnosis
    will make sure that people who need it, get it.

        I have introduced legislation with Senators Capito, Menendez, and
    19 others called the CHANGE Act, which will encourage timely and
    accurate detection and diagnosis using evidence-based tools.

        Finally, while working toward a cure, we must not forget the people
    who care for their loved ones with the disease, and we all know that
    Alzheimer's really is a family disease.

        I am so glad that my HOPE for Alzheimer's Act was implemented on a
    bipartisan basis, and now newly diagnosed Alzheimer's patients can
    access a doctor's visit to create an individual care plan. However, not
    everybody knows of this benefit, and not everyone is using it. My
    Improving HOPE for Alzheimer's Act, cosponsored by 47 members, many on
    this subcommittee, requires HHS to conduct a nationwide campaign to
    increase awareness of this care planning visit and the importance of
    supporting families.

        We also must ensure that once patients and their caregivers have a
    plan, that they can actually implement the plan. That's why I will be
    introducing legislation next year--and I welcome my colleagues to be a
    part of this--directing the Department of Health and Human Services to
    test a payment model to support coordinated care for dementia patients,
    as well as support for caregivers. By coordinating care, we can reduce
    complications and ensure that families have resources to help care for
    their loved ones.

        So I'm very proud of the progress we have made, and the work we are
    doing together on a bipartisan basis, but there is so much more to do.
    And I look forward not only to today's discussion, but also for ways we
    can continue to work together on diagnosis, treatment, and ultimately,
    what we all want, which is a cure for Alzheimer's.

        Thank you, Mr. Chairman.

                                     ______

                                 Communications

                                  ----------

                         Arizona Alzheimer's Consortium

                  Statement of Eric M. Reiman, M.D., Director

       ADVANCIING THE SCIENTIFIC AND CLINICAL FIGHT AGAINST ALZHEIMER'S
                                    DISEASE

        Thank you for the invitation to provide my thoughts about the fight
    against Alzheimer's disease, and thank you and your colleagues for your
    wonderful support of our efforts to address this problem here in
    Arizona. My name is Eric Reiman. I am Executive Director of Banner
    Alzheimer's Institute and CEO of Banner Research, Professor of
    Psychiatry at the University of Arizona, University Professor of
    Neuroscience at Arizona State University, Clinical Director of the
    Neurogenomics Division at TGen, and Director of the Arizona Alzheimer's
    Consortium.

        Allow me to begin with the bad news:

        Alzheimer's disease (AD) is the most common form of disabling
    memory and thinking problems (i.e., ``dementia'') in older people. It
    affects nearly 10% of those over the age of 65 and between a third and
    half of those over age 85. It takes a devastating to toll on the
    affected person and an intolerable toll on family caregivers. Due to
    the growing number of people living to older ages, the number of people
    with Alzheimer's dementia is expected to triple in the next 30 years,
    such that it is expected to account for disabling memory and thinking
    problems in more than 100 million patients and have an overwhelming
    impact on countries around the world. According to an Alzheimer's
    Association report, the number of affected persons is growing at a
    faster rate in Arizona than in any other state in the country.

        We have a woefully inadequate standard of dementia care for
    patients and their families. 60% of patients with dementia never have
    an evaluation, diagnosis or exclusion of potentially reversible
    contributions to their memory and thinking problems. Too many people,
    including many clinicians, think there is nothing you can do about the
    problem, not recognizing the range of coping strategies, non-medical
    management options that are available to support the patient and their
    families. Meantime, we still need more effective medication strategies
    to improve a person's cognitive symptoms, manage their distressing
    behavioral symptoms like agitation and paranoid delusions, and we need
    a compensated user friendly way to help patients and family caregivers
    navigate the range of issues and daily living, safety, financial,
    legal, medical, assisted living, and social resources that they may
    face after a diagnosis.

        While there has been great research progress, we have not seen a
    new medication therapy for Alzheimer's disease approved since 2003, and
    about 99% of studied treatments since that time have failed to work. We
    have needed the public policies, state and federal funding, and public-
    private partnerships needed to create a much more successful drug
    development paradigm and encourage makers of promising treatments to
    spend the funds and take the years needed to put promising disease-
    stopping and prevention therapies to the test; we have needed
    biological indicators of a drug's efficacy to inform the development of
    those drugs with the greatest chance of success; we have needed new
    strategies to accelerate the evaluation and approval of prevention
    therapies, which are started before the disease has ravaged the brain.
    While this is far more to do, we have seen major progress in each of
    these areas.

        Looking ahead, we need to anticipate what it will take to optimize
    the accessibility and affordability of effective treatments when they
    become available. While there has been exciting progress in the
    development of brain imaging and spinal fluid biomarkers of AD, their
    accessibility has been limited by the cost of PET scans, relatively
    uncommon performance of sometimes uncomfortable lumbar punctures (i.e.,
    spinal taps), and an interest on the part of CMS to demonstrate the
    value of these diagnostic techniques in the clinical setting before
    approved disease modifying treatments are available.

        Now, some good news:

        In the last decade, researchers have made substantial progress in
    the scientific fight against AD. We have identified processes involved
    in the development of the microscopic abnormalities that are used to
    support the diagnosis of AD at the end of life, including amyloid
    plaques, tau tangles, and a characteristic and progressive loss of
    neurons and their connections. We have identified nearly 30 genetic
    risk factors, as well as potentially modifiable non-genetic risk
    factors that can be targeted by new treatments, including both drug and
    emerging gene therapies. We have recently demonstrated the potential of
    blood tests to diagnosis, detect and track AD, inform a person's
    prognosis and management, and further inform the evaluation of
    promising disease-modifying and prevention therapies. We have seen more
    interaction between basic science researchers, clinical researchers and
    big data scientists to generate molecular models that are informed by
    changes observed in the human brain, including potential drivers of
    those networks that have been suggested to account for the pathological
    features of AD and which could be targeted by new investigational drugs
    or already available drugs that could be repurposed for the treatment
    and prevention of AD. I expect to see the use of extremely large-scale
    electronic health record data and big-data techniques-in people who do
    or do not have AD blood tests-to provide a complementary way to find
    new treatments.

        In my opinion, three research developments may turn out to be
    particularly impactful when it comes to advances in the research, drug
    development and clinical settings:

        (1) Development of promising blood tests of AD and its different
    neuropathological (amyloid, tau, inflammatory, degenerative and
    related) features. These blood tests could begin to impact research
    studies and clinical trials in the coming year, have a major impact on
    affordable and widely accessible diagnosis and management of AD and
    related dementias within the next 2-3 years, and provide a way to
    ensure the widespread accessibility and affordability of AD prevention
    therapies, if they are proven to be effective, by 2025. Imagine the
    chance to increase the likelihood that primary care physicians would
    ask about memory and thinking problems, order a blood test to support a
    symptomatic person's diagnosis, prognosis and management, hand off the
    patient and family to affordable and accessible navigators to gather
    additional information about a person's memory and thinking abilities,
    communicate what the test results mean, and help the family with
    important decisions and resources such that they are not left in the
    lurch to address their challenges on their own. Imagine the chance to
    conduct a blood test every two years after age 50 to help identify
    those people who would benefit from an effective AD prevention therapy.
    We still need to see those diagnostic tests reimbursed, before or after
    a
    disease-slowing treatment becomes available, and we still need to see
    navigator services developed, including those that can be provided
    virtually, and reimbursed to have the greatest impact on patients and
    family caregivers. I expect to see major progress in each of these
    areas in the next 2-5 years.

        (2) Suggestive but not yet definitive evidence that some amyloid-
    reducing therapies may slow the progression of AD in persons with
    symptoms. If confirmed (whether or not the first amyloid-reducing
    antibody drug aducanumab is approved for restricted use in March 2021),
    effective treatments would provide a shot in the arm for patients and
    families, provide support for the still debated contributions of
    amyloid to the development of the disease, and clarify which of the
    treatments biological (PET, spinal fluid and blood test) effects are
    associated with a clinical benefit, such that those biological
    measurements could inform and accelerate the evaluation of new disease-
    stopping and prevention therapies.

        (3) We are just beginning to see more diverse treatments under
    consideration in drug discovery and drug development. These include
    several strategies to slow down or reverse the accumulation of
    potentially harmful amyloid proteins, the spread of potentially harmful
    tau proteins, and some of the neuroinflammatory and degenerative
    changes also found in the disease. We are also excited about emerging
    gene therapies, including those that modify or turn off the expression
    of APOE4, the major genetic risk factor for developing AD at older
    ages-and we look forward to possibility to put some of those gene
    therapies to the test within the next 2-3 years.

        Given the magnitude of the problem, some of the challenges involved
    in AD research. and the failure to find effective AD-modifying
    treatments so far, researchers from academia and industry, NIH and
    other funding agencies, FDA and other regulators, the Alzheimer's
    Association and other stakeholder groups--and policy makers
    themselves--have recognized the idea that when it comes to the fight
    against AD, we are all in this together. They have developed new ways
    to work together and support shared goals and, following approval of
    the National Alzheimer's Care Act (NACA) in 2012, there has been nearly
    a ten-fold increase in research funding, helping to attract the best
    and brightest minds to this endeavor. I'm pleased to report that those
    funds are being used in strategically compelling and sometimes bold
    ways, and with clear measures of accountability. I expect that we will
    see dividends of this and other investments sooner than some might
    think.

    Arizona's Leadership Roles

        Thanks in large part to you, Arizona has been a leader in the fight
    against AD. With your support, Arizona's researchers were the first to
    demonstrate the ability to detect and track AD years before the onset
    of symptoms. They have provided critical resources to support the
    validation and FDA approval of amyloid PET and tau PET scans in the
    diagnosis of cardinal AD features, and it has recently used some of its
    resources to demonstrate the accuracy of a promising blood tests and
    their potential to revolutionize the field. They have launched a new
    era in AD prevention research, forged ground-breaking research
    strategies, methods and enrollment strategies to accelerate the
    evaluation and approval of a prevention therapy, and provided the best
    possible chance to find and support the approval of an effective AD
    prevention therapy within the next five years. Arizona researchers are
    world leaders in the study of the aging brain, they have generated
    invaluable resources of data and biological samples for the study of
    AD, related brain disorders and normal aging to researchers around the
    world-including those volunteers in our Brain Donation Research Program
    and those at different levels of genetic risk. They have been leaders
    in the evaluation of investigational drug therapies, they established
    the Alzheimer's Prevention Initiative, which includes the first NIH and
    industry supported AD prevention trials. They have a chance to find an
    effective AD prevention therapy by 2025, fulfilling a primary goal of
    the National Plan to Address AD.

        We have capitalized on the collaborative efforts of nearly 200
    researchers from 11 organizations and many different scientific
    disciplines in the state and institutionally supported Arizona
    Alzheimer's Consortium to address our goals. The Consortium provides
    the glue that binds us together and the fuel needed to propel new
    collaborative research institutions. Its researchers include world
    leaders in brain imaging and blood-based biomarkers, computational and
    statistical data analysis, the basic, cognitive and behavioral
    neurosciences, experimental therapeutics and clinical trials, and
    clinical and neuropathology research, and dementia care. They have made
    pioneering contributions to the field, they are internationally known
    for its collaborative model and leadership roles, and with your
    support, they have made Arizona a destination center for the fight
    against AD.

        Arizona's elected officials and its partners at the Arizona
    Department of Health Services recognized the importance of this problem
    and the chance to make a difference right here in Arizona, and they
    have supported this effort since 1998--long before any other state or
    the federal government itself. There is a lot more that needs to be
    done to advance AD research, find and support the development of new
    treatments, support the development of medication and non-medication
    prevention therapies, address both the medical and non-medical needs of
    patients and their families, and do so in highly accessible and
    affordable ways. Thanks to you and your colleagues, we have a chance to
    have a transform AD research, the development of effective treatments,
    and clinical care, and we have a chance to find an effective prevention
    therapy in the next few years.

                                     ______

                          Life Molecular Imaging Inc.

                            75 State Street, Floor 1

                                Boston, MA 02109

                            Email: info@life-mi.com

                           Web: https://life-mi.com/

        Today, Alzheimer's disease is usually diagnosed after an already
    symptomatic patient with a cognitive impairment undergoes an extensive
    clinical diagnostic workup. This workup typically includes family and
    medical history, physical and neurological examinations, psychiatric
    screen, laboratory tests and imaging procedures such as computed
    tomography (``CT'') or magnetic resonance imaging (``MRI'') scans.
    However, despite advances, we are still far from being able to assess
    patients more accurately and earlier in the course of their disease and
    determine if the underlying cause of the presenting cognitive
    impairment is due to Alzheimer's disease. In fact, a definitive
    diagnosis of Alzheimer's disease was only made post-mortem by looking
    for and identifying the presence of beta-amyloid plaques and
    neurofibrillary tangles in the patient's brain. We now know that
    despite these advances, post-mortem studies looking for Alzheimer's
    disease pathology have shown that 10-30% of diagnoses based on clinical
    examinations alone are incorrect. Through inaccurate diagnosis, we miss
    the opportunity to better manage and provide care for these patients.

        Amyloid positron emission tomography (``PET'') imaging can help to
    ensure the early detection and diagnosis of Alzheimer's disease. Life
    Molecular Imaging (``LMI'') is one of three companies with a U.S. Food
    and Drug Administration (``FDA'')-
    approved diagnostic radiopharmaceutical indicated for PET imaging of
    the brain to estimate beta-amyloid neuritic plaque density in patients
    with cognitive impairment who are being evaluated for Alzheimer's
    disease and other causes of cognitive decline. Amyloid PET imaging is
    aimed at bringing Medicare beneficiaries a diagnostic test for early
    detection of one of the key neuropathologies of Alzheimer's disease,
    leading to a better quality of life.

        The Centers for Medicare and Medicaid Services (``CMS'') is taking
    steps to provide patients and their physicians with new potential
    coverage of amyloid PET imaging to detect beta-amyloid, a hallmark of
    Alzheimer's disease. CMS issued a Medicare National Coverage
    Determination (``NCD'') on September 27, 2013, which allows conditional
    coverage of amyloid PET under Coverage with Evidence Development
    (``CED'') studies. In 2016, the Imaging Dementia--Evidence for Amyloid
    Scanning (``IDEAS'') Study was initiated as a CED trial for amyloid PET
    imaging. A second CED study, known as New IDEAS will enroll 7,000 new
    Medicare-eligible patients.

        The original IDEAS Study enrolled more than 18,000 Medicare
    beneficiaries and provided evidence that amyloid PET imaging can change
    medical management in 60.2% of mild cognitive impairment patients and
    63.5% of dementia patients of uncertain etiology. It also found that
    diagnosis changed in 35.6% of patients. This resulted an increase in
    diagnostic confidence and a decrease in utilization of alternative
    diagnostics.

        The results of the IDEAS Study provide compelling evidence that
    there is a health benefit to getting an accurate and early diagnosis.
    When patients and caregivers learn of their diagnosis, earlier planning
    for the patient can occur, patients are able to enter clinical trials,
    receive appropriate therapeutic treatment, and possibly delay entering
    nursing homes. Many therapeutic candidates have not been successful
    because clinical trials have not included the correct patients. To
    appropriately test anti-Alzheimer's disease drugs, clinical trial
    participants must have Alzheimer's disease. Prior to amyloid PET
    imaging, 30-40% of patients were incorrectly enrolled. Driving the
    correct patients into clinical trials can help lead to a cure for
    Alzheimer's disease.

        While there may be no cure for Alzheimer's disease today, symptoms
    are treatable. Ensuring early detection and accurate diagnosis of
    Alzheimer's disease will increase access to long-term services and
    supports that assist people with dementia and their caregivers in their
    home.

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