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107th Congress
Session I | Session II
Testimony on Alzheimer’s Disease Research
Richard J. Hodes, M.D.
Director, National Institute on Aging
April 30, 2002
Senator Harkin and Members of the Committee:
Thank you for inviting me to appear before you today to discuss Alzheimer’s disease (AD), an
issue of interest and concern to us all. I am Dr. Richard Hodes, Director of the National
Institute on Aging (NIA), the lead federal agency for Alzheimer’s disease research. I am
delighted to be here this morning to tell you about the progress we are making toward
understanding, treating, and preventing AD.
As you know, AD is a major public health issue for the United States, and it has a devastating
impact on individuals, families, the health care system, and society as a whole. Approximately 4
million Americans are currently battling the disease, with annual costs estimated to exceed $100
billion. Moreover, the rapid aging of the American population threatens to increase this burden
several-fold in the coming decades. However, despite the grim statistics, we have made, and
are making, tremendous progress.
Until very recently, preventing or curing AD was considered, at best, a distant possibility. Our
understanding of AD's underlying biology was limited, and for this reason it was difficult even to
predict what might be effective as a treatment or preventive.
Today, the picture is considerably brighter. Through laboratory and population-based scientific
studies, we have identified a number of risk factors for AD, including both genetic and possible
lifestyle factors. Research supported by the NIA, the National Institute of Neurological
Disorders and Stroke (NINDS), and the National Institute of Mental Health (NIMH) has
identified several genes that can cause AD, thereby helping us identify pathways affecting its
development or progression, which will lead to better molecular predictors of the disease even
before it is clinically apparent. The development and refinement of powerful imaging techniques
that target anatomical, molecular, and functional processes in the brain will give us an improved
ability to diagnose AD early, while the patient can still take an active role in decision-making.
These techniques, along with better neuropsychological tests, are also enabling us to identify
people who are at very high risk of one day developing the disease and to determine just how
the disease starts in brain. This knowledge, in turn, may allow early intervention in persons long
before the disease affects their level of functioning.
Most importantly, we are making significant advances toward effectively treating, or even
preventing, AD. (Chart #1) NIA is currently supporting 18 AD clinical trials, seven of which
are large-scale prevention trials. These trials are testing agents such as estrogen, anti-inflammatory drugs, and anti-oxidants for their effects on slowing progress of the disease,
delaying AD's onset, or preventing it altogether. We eagerly await the results of these trials.
As we search for effective preventive interventions and treatments for AD, it is becoming clear
that, rather than seeking only a “magic bullet” that will, by itself, prevent or cure the disease, we
may be able to identify a number of potential interventions that together can be used to reduce
risk. Several recent studies have highlighted this.
For example, a recent study in the New England Journal of Medicine indicates that elevated
blood levels of the amino acid homocysteine, already considered a risk factor for
cardiovascular disease, are associated with an increased risk of developing AD. (Chart #2)
The relationship between AD and homocysteine is of particular interest because blood levels of
homocysteine can be reduced, for example, by increasing intake of folic acid (or folate) and
vitamins B6 and B12. And, in fact, in a separate study in the Journal of Neuroscience, NIA
researchers show that folic acid may protect AD transgenic mice against death of neurons in
one of the brain regions most affected in AD. NIA has ongoing clinical trials of these substances
to test whether supplementation can slow the rate of cognitive decline in cognitively normal men
as well as in women at increased risk for developing heart disease. A pilot clinical trial to
determine effective treatment levels of folate/B6/B12 for lowering plasma homocysteine levels
in persons with AD is ongoing, and a full-scale clinical trial on people diagnosed with AD is due
to start in 2003. Other studies have indicated that the use of statins, the most common type of
cholesterol-lowering drugs, may lower the risk of developing AD (Chart #3). A clinical trial to
determine whether statins slow the rate of disease progression in AD patients is planned for fall
2002.
Another promising area of study is the role of mentally stimulating activities throughout life as a
factor capable of maintaining cognitive health or even reducing the risk of cognitive decline or
AD. Through its Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)
study, NIA is currently exploring whether three specific interventions (on memory, reasoning,
and speed of processing) can maintain or improve functioning in unimpaired, community-dwelling older adults. In addition, NIA-supported researchers recently found that more
frequent participation in activities such as reading, doing crossword puzzles, or playing card
games is associated with a reduced risk of later developing AD.
In addition to these exciting clinical findings, NIA-supported investigators are beginning to
unravel AD's complex etiology. For example, until very recently, just four of the approximately
30,000 genes in the human genome were conclusively known to affect the development of AD
pathology. Three of these genes cause early onset AD, and only one is associated with the
more common form of the disease, late-onset AD (LOAD). Recent genetic studies suggest that
as many as four additional and as yet unidentified genes may also be risk factors for LOAD,
and regions in several different chromosomes have been identified as likely locations for these
genes. Finding new risk factor genes will help identify pathways affecting the development or
progression of AD and may eventually lead to better predictors of the disease even before it is
diagnosed.
To facilitate the identification of the remaining AD risk factor genes, NIA is planning an
expansion of its National Cell Repository. A national resource for research on AD, the
Repository was created to collect and distribute DNA, cells, and information from families with
multiple members with AD and related dementias. Its activities include the production of a
catalog of cell lines and DNA samples that are available for qualified scientists to study. The
expansion will allow researchers to more rapidly identify the underlying genetic mechanisms and
environmental risk factors that interact to cause the more common late-onset form of AD.
Understanding these mechanisms will provide opportunities for the design of effective
diagnostic, therapeutic, and preventive interventions.
The process of translating basic science findings into clinical interventions is a challenging but
critical component of AD research. (Chart #4) For example, a promising finding gained
through basic research efforts was the ability of an immunization strategy to prevent or reverse
formation of amyloid plaques in mouse models of AD. In collaboration with NINDS, NIA has
issued a Request for Applications (RFA) and funded a number of studies to better understand
the science underlying the vaccine approach. Similarly, NIA-funded studies are providing
exciting new evidence on the identity of the snipping enzyme that cuts the amyloid beta molecule
out of its precursor protein, and ways to blunt its activity. These interventions may be capable
of preventing the formation of amyloid plaques.
In addition, NIA-supported researchers have recently made a surprising discovery about the
role of amyloid plaques in AD pathology. (Chart #5) In one study, investigators found that
amyloid beta oligomers, or small precursor components of amyloid plaques, inhibited brain
mechanisms thought to be involved in memory formation in rats. In another, scientists used an
immunization strategy to treat plaque-containing AD transgenic mice. Although the amount of
plaques in the mice’s brains remained constant, the mice very quickly regained cognitive
functioning. These findings suggest that amyloid plaques themselves may not be responsible
for AD's cognitive symptoms, and that a related pathology – perhaps a precursor molecule
such as the amyloid beta oligomer– is the true culprit. This insight, in turn, may lead to the
development of new and effective treatments for the disease.
Although the findings are still preliminary, these studies illustrate the importance of continued
basic research to help us understand the mechanisms behind AD development and pathology,
and the ways in which basic research findings can suggest new prevention and treatment
strategies.
Scientists funded by NIA, NINDS, and NIMH are also developing and refining powerful
imaging techniques that hold promise of earlier and more accurate diagnosis of AD, as well as
improved identification of people who are at risk of developing the disease and a more
complete understanding of normal and abnormal age-related changes in the brain. (Chart #6)
For example, recent studies suggest that positron emission tomography (PET) scanning of
metabolic changes in the brain and magnetic resonance imaging (MRI) scanning of structural
brain changes may be useful tools for predicting future decline associated with AD and other
neurodegenerative diseases.
Researchers have also developed a new way of using functional MRI (fMRI),
a technique for visualizing activity of brain structures that
is both easier on the person being tested and capable of imaging
smaller structures in the brain than has been possible in
the past. Using this new technique, investigators assessed
the hippocampus, an area of the brain involved in memory formation,
in people between 20 and 88 years of age. They found that
activity in certain regions of the hippocampus declines normally
with age, but that decline in a specific region, the entorhinal
cortex, is abnormal and may reflect an illness or condition
such as AD. They conclude that some age-related memory loss
is normal, due to ordinary hippocampal changes, but that individuals
with dysfunction in the entorhinal cortex may be at increased
risk of progressing to full-blown AD. These studies, if confirmed
by ongoing longitudinal observation of the patients, hold
the promise, for the first time, of being able to distinguish
between the subtle brain changes that occur with normal aging
and those that are a harbinger of clinical AD.
These methodologies may also be useful for evaluating the efficacy of drugs in stemming the
progression of AD or preventing its onset altogether. However, these and other emerging
imaging techniques, while promising, require further testing and analysis before they can be
routinely adopted in the clinical setting.
Another very important area of research involves easing the burden on caregivers of AD
patients. In a sense, the AD “patient” is not only the person with the disease, but the entire
family unit. Most Americans with AD are cared for outside the institutional setting by an adult
child or in-law, a spouse, another relative, or a friend. The financial costs of this care can be
devastating to families; the average lifetime cost per person for patients with AD is
approximately $174,000. In addition to these financial burdens, caregivers frequently
experience emotional stress and physical strain.
NIA is investing in new approaches to assist these caregivers. A first priority is to assess the
magnitude of the problem. For example, the ongoing Aging, Demographic, and Memory Study
(ADAMS) has been designed to assess dementia and AD among Americans, the burden on
caregivers, the economic cost of dementia to families and to society, and the burden of
dementia over the course of the illness.
NIA is also supporting a study of a combined behavioral and drug intervention on patients with
mild AD. In this study, caregivers will be key participants in the behavioral intervention, and the
researchers hypothesize that this participation will reduce caregivers’ psychological stress. In
addition, NIA is supporting a large, multi-site clinical trial, REACH (Resources for Enhancing
Alzheimer’s Caregiver Health), to examine the effectiveness of various interventions to
strengthen family members’ capacity to care for individuals with AD. Thus far, the study has
recruited over 1200 caregiver/care recipient pairs at six different sites across the country to
participate in 12 different interventions. REACH is designed to show us what works to support
caregivers and at what cost; we anticipate that the first findings from this trial may be available
within the next several years. The NIMH is supporting a major project called the Clinical Anti-psychotic Trial of Intervention Effectiveness for Alzheimer’s Disease (CATIE-AD) designed to
help identify effective treatments for behavioral problems in AD and to help reduce the burden of
care for both providers and families.
Fifteen years ago, we did not know any of the genes that could cause AD, and we had no idea
of the biological pathways that were involved in the development of brain pathology. Now, we
know the 3 major genes for early-onset disease and one of the major risk factor genes for late-onset disease, and we have extensive knowledge of pathways leading to the development of
AD's characteristic amyloid plaques in the brain. Ten years ago, we could not model the
disease in animals. Today, transgenic mice are an invaluable resource for modeling amyloid
plaque development in the brain and in testing possible therapies. Five years ago, we did not
have any prevention trials funded and had no ways of identifying persons at high risk for the
disease. Now, we have seven ongoing prevention trials, and scientists are identifying persons at
high risk for developing AD by imaging, neuropsychological tests, and structured clinician
interviews. And as recently as one year ago, we did not understand anything about how
plaques and tangles relate to each other. Now, through the creation of the first double
transgenic mouse to produce both plaques and tangles, we know that plaques in the brain can
influence the development of tangles in brain regions susceptible in AD. Recent findings also
suggest that there are some common mechanisms of disease in a number of neurodegenerative
disorders, which will further inform research in AD.
It is difficult to predict the pace of science or to know with certainty what the future will bring.
However, the progress we have already made will help us speed the pace of discovery, unravel
the mysteries of AD's pathology, and develop safe, effective preventions and treatments, to the
benefit of older Americans.
Thank you for giving me this opportunity to share with you our progress on Alzheimer’s
disease. I would be happy to answer any questions you may have.
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