[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                     
          
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                          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: [email protected]

                       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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