[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
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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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