Testimony
Statement by
Richard J. Hodes, M.D. Director, National Institute on Aging
on
Alzheimer's Disease Research
The Senate Appropriations Subcommittee on Labor, Health and Human Services, and Education
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March 23, 2004
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
today to tell you about the progress we are making toward
understanding, treating, and preventing AD.
As you know, AD is a devastating condition with a profound impact
on individuals, families, the health care system, and society as a
whole. Approximately 4.5 million Americans are currently battling
AD, with annual costs for the disease estimated to exceed $100
billion.
Moreover, the rapid aging of the American population threatens to
increase this burden significantly in the coming decades:
Demographic studies suggest that if current trends hold, the annual
number of incident cases of AD will begin to sharply increase
around the year 2030, when all the baby boomers (born between 1946
and 1964) will be over age 65. By the year 2050, the number
of Americans with AD could rise to some 13.2 million, an almost
three-fold increase.
But these numbers, however stark, do not tell the whole
story. Although AD remains a major public health issue for
the United States, we have made, and are continuing to make,
dramatic gains in our ability to understand and diagnose AD that
offer us the hope of preventing and treating the disease, to
reverse the current trends. As a part of our Government and
Performance Results Act, NIH has developed a long-term, high-risk
goal of identifying at least one clinical intervention that will
delay the progression, delay the onset, or prevent Alzheimer's
disease.
Risk Factors
Many Americans wonder whether they or their loved ones are at risk
of developing AD. Sadly, as they age, many of them will
be. The risk of AD increases dramatically with age, with
nearly half of all individuals over age 85 being diagnosed. Many older Americans
struggle with mild cognitive impairment (MCI), a condition that is
frequently a precursor to AD; in one recent population-based study
of cognition in the elderly, 22 percent of participants over 75,
and 29 percent of those over 85, were diagnosed with MCI. Determining who is at
high risk of developing AD and who is not – and why -- will
enable us to identify potential targets for preventive
intervention, as well as those individuals who might benefit most
from such interventions.
Through laboratory, clinical and population-based research, we have
identified a number of risk factors for AD, including both genetic
and lifestyle factors. We already know of three major genes
for early-onset disease and have identified a major risk factor
gene, ApoE4, for the more common late-onset disease. Recent
findings are enabling us to close in on several others, thought to
be on chromosomes 9, 10, and 12.
However, neuroscientists have become increasingly interested in a
specific set of genes that may influence not whether, but when, a
person might develop symptoms of neurodegenerative disease.
Delaying the onset of AD symptoms by even five years could greatly
reduce the numbers of people who will have the disease, as well as
providing additional cognitively-healthy time to those who will
eventually be diagnosed.
Recently, NIH-supported investigators found a gene on chromosome 10
that they believe influences the age of onset of both
Alzheimer’s disease and Parkinson’s disease. Using a
novel method to match the genes of people affected with these
diseases with the age at which study participants started
developing symptoms, the scientists found that one gene, GSTO1, was
significantly associated with late onset of both Alzheimer’s
and Parkinson’s. This important work gives us new clues to
the role of genetics in the timing of late-life forms of these
devastating neurodegenerative diseases.
Last year this Committee heard about the NIA’s AD Genetics
Initiative, a program to accelerate the pace of AD genetics
research by creating a large repository of DNA and cell lines from
families with multiple AD cases. The goal of
this initiative is to develop strategies for identifying the
additional late-onset AD (LOAD) risk factor genes, associated
environmental factors, and the interactions of genes and the
environment. The NIA’s AD Genetics Initiative will
intensify sample collection and encourage data sharing by providing
access to a national repository to qualified investigators.
This year, we have launched several well-integrated components of
the Genetics Initiative. Mechanisms to efficiently identify and
share large numbers of samples for AD genetic analysis have been
developed through the recently-enlarged National Cell Repository
for AD (NCRAD), and eighteen of the NIA’s Alzheimer’s
Disease Centers (ADCs) have received supplemental funding to
recruit new family members for participation. Uniform
standards for sample collection have also been developed.
In order to publicize the initiative, the NIA Office of
Communications and Public Liaison, together with its
Alzheimer’s Disease Education and Referral Center, Columbia
University, and NCRAD, partnered with the Alzheimer’s
Association to conduct focus groups and develop materials to
publicize the initiative and help recruiting efforts. These
publicity materials, including a workbook, CD ROM, fact sheet, and
brochure were distributed at a recent meeting of all
Alzheimer’s centers and have been sent to ADCs and
Alzheimer’s Association chapters to further recruitment
efforts.
As of Late January, over 200 families, of the approximately 1000
needed, have been evaluated and are now enrolled in the study, and
over 800 blood samples have been logged at NCRAD. Working
groups have been established which are helping to determine the
most useful phenotypic data to be included in the data bank along
with the biological samples. A major goal is the long-term
follow-up of individuals participating in the study.
Type 2 diabetes, which, according to the American Diabetes
Association, affects approximately 17 million Americans, is another
potential risk factor for cognitive decline and AD. In a
recent study, researchers found that compared to older non-diabetic
women, older women with type 2 diabetes were about 30 percent more
likely to score poorly on tests of cognitive function, and that the
risk increased with the duration of their condition. However,
the diabetic women in the study who took glucose-lowering pills had
a risk similar to non-diabetic women. Recognizing the
potential link between type 2 diabetes and cognitive decline, NIA
researchers are currently participating in an offshoot of the
National Heart, Lung, and Blood Institute’s Action to Control
Cardiovascular Risk in Diabetics (ACCORD) study. ACCORD evaluates
whether more intensive glucose, blood pressure and lipid management
can reduce cardiovascular disease in people with diabetes; the aim
of this sub-study, ACCORD-MIND, is to test whether the rate of
cognitive decline and structural brain change in people with
diabetes treated with standard care guidelines is different than in
people with diabetes treated with intensive care guidelines.
Recruitment for the ACCORD study began in January 2003, and we
anticipate that 2800 people will participate in ACCORD-MIND.
Imaging
Powerful imaging techniques, including positron emission tomography
(PET) and magnetic resonance imaging (MRI), are opening a window
into the brain, allowing us to visualize not only anatomical
structures but also functional processes and activities at the
molecular level. The refinement of these techniques continues
to have a profound effect on all areas of AD research.
For example, improvements in brain imaging, coupled with the
development of more sensitive cognitive tests, are enabling us to
diagnose AD in the research setting with greater precision than
ever before, despite the fact that there remains no scientifically
validated method to visualize AD’s characteristic amyloid
plaques and neurofibrillary tangles in a living human.
However, even this may be changing. Researchers have recently
developed the first radiotracers, including a molecule called
Pittsburgh Compound-B, that facilitate visualization of amyloid
deposition in living AD patients using PET scans (Chart # 1).
Although further research is needed, these molecules may eventually
offer us a powerful and accurate diagnostic tool for the
disease.
Visualization of brain structures and activities may also enable us
to identify people at risk of developing the disease even decades
before the onset of symptoms. In a recent study,
investigators used positron emission tomography (PET) to examine
the brains of asymptomatic young adults (ages 20-39) who were
carriers of the APOE-e4 gene, a common susceptibility gene for
late-onset AD. Middle-aged carriers of this gene are known to
have abnormally low rates of metabolism in the same brain regions
as patients with AD; in this study, the investigators found the
same brain abnormalities in the younger carriers of the gene.
The precise link between the APOE-e4 gene, the altered metabolism,
and AD remains unknown, and more research is needed on this
provocative finding, but it may offer important clues to AD’s
etiology and perhaps even a target for future prevention efforts.
Advances in imaging also have the potential to speed our basic
understanding of the disease -- for example, to determine which
pathological features of AD (plaque and tangle development, cell
death, loss of connections between neurons) best correlate with
cognitive loss. Improved imaging techniques may further
enable us to visualize the effects of therapeutic interventions
more rapidly and accurately, with the potential for making AD
clinical intervention trials smaller, faster and more affordable.
Last year, we told this Committee about our plans for a
Neuroimaging Initiative, a longitudinal, prospective, natural
history study of normal aging, mild cognitive impairment, and early
AD to evaluate neuroimaging techniques such as MRI and PET, as well
as other biological markers. This year, I am pleased to tell you
that work on the Initiative is underway. We have issued a
Request for Applications and have received submitted applications.
In addition, we have secured the participation of several key
industry participants. Awards will be made this summer, with
work on the project to begin shortly thereafter. The study
objectives are to:
Identify the best markers for early diagnosis of AD
Identify markers for following disease progression and monitoring
treatment response
Develop surrogate endpoints for clinical
trials
Decrease time and expense of drug development
Establish methods for the collection, processing, and distribution
of neuroimaging data in conjunction with other biological,
clinical, and neuropsychological data
The initiative is planned as a partnership among the NIA/NIH,
academic investigators, the pharmaceutical and imaging equipment
industries, the Food and Drug Administration, the Centers for
Medicare and Medicaid Services, and the NIH Foundation, with
participation from the Alzheimer’s Association and the
Institute for the Study of Aging. The clinical, imaging, and
biological data and samples will be made available, with
appropriate safeguards to ensure participant privacy, to all
scientific investigators in the academic and industrial research
communities.
Prevention and Treatment
As imaging and laboratory studies tell us more about AD’s
pathology, we are identifying a number of novel molecular
characteristics that may prove to be targets for treating the
disease or preventing it altogether. For example, enhancing
the brain’s self-protective capacity by inducing production
of naturally-occurring proteins that destroy beta amyloid shows
promise in mice that have been genetically altered to produce
amyloid plaques. In a recent study, boosting production of
two proteins, insulin-degrading enzyme and neprilysin, in neurons
of these mice reduced brain amyloid levels, slowed or even
prevented amyloid plaque formation, and prevented their premature
death (Chart # 2).
In this endeavor, animal models – particularly transgenic
mice, but also worms, dogs, and even non-human primates – are
invaluable research resources for studying age-related and
disease-related changes in the brain and for testing promising
interventions. For example, investigators recently studied the
effects of an enriched diet on age-related cognitive decline in
dogs, a model that mimics the behavioral and brain pathological
declines of older humans more closely than rodent models.
Young and old dogs were given a series of baseline cognitive
tests. Half of each age group then remained on a standard
diet, while the other half of each age group was placed on a diet
enriched with antioxidants and mitochondrial co-factors, which are
thought to improve nerve cell energy and efficiency and decrease
production of molecules that contribute to oxidative damage in the
brain. Animals remained on their respective diets for six
months and then were assessed again for cognitive performance on a
variety of tasks. When tested, old dogs on the control diet
learned more slowly than the young dogs and made significantly more
errors; however, when compared to the old animals on the control
diet, old animals on the enriched diet showed significantly better
learning, although not to the level of the younger animals.
The success of this simple, cost-effective intervention has
significant implications for dietary interventions that might
lessen or even prevent some of the cognitive decline seen with age
and with disease; a pilot trial of similar antioxidants in older
Down syndrome patients who have developed AD is currently under
way.
In fact, NIA is currently supporting 25 AD clinical trials,
including large-scale prevention trials, which are testing agents
such as hormones, anti-inflammatory drugs, statins,
homocysteine-lowering vitamins, and anti-oxidants for their effects
on slowing progress of the disease, delaying AD’s onset, or
preventing the disease altogether. Other intervention trials are
assessing the effects of various compounds on the behavioral
symptoms (agitation, aggression, and sleep disorders) of people
with AD.
Caregiving
Most of the over 4 million Americans with AD today are cared for
outside the institutional setting by an adult child or in-law, a
spouse, another relative, or a friend. Caregivers frequently
experience significant emotional stress, physical strain, and
financial burdens, yet they often do not receive adequate support
for their remarkable efforts. Several recent studies have
explored the problems faced by caregivers of AD patients, and have
sought to design interventions to reduce their burdens.
Although family caregiving has been extensively studied, there has
been less research on the impact of end-of-patient-life
on caregivers who are family members of persons with
dementia or to the caregivers' responses to the
death of the patient. As part of the NIA=s
Resources for Enhancing Alzheimer=s Caregiver Health (REACH) study,
a multisite randomized clinical intervention of 1222 caregiver and
recipient dyads, investigators assessed the type and intensity of
care provided by 217 family caregivers to persons with
dementia during the year before the patient's death,
as well as the caregivers' responses to the
death. Additionally, this group was compared to the 180
caregivers who institutionalized their family member. The
researchers found that the in-home caregivers reported tremendous
levels of stress in the year leading up to the care recipient=s
death, and that levels of caregiver depression Aspiked@ immediately
following the care recipient death. However, the caregivers
in this study demonstrated tremendous resilience: Within fifteen
weeks of the recipient=s death, depression returned to pre-death
levels, and within one year, depression was significantly lower
than prior to the care recipients’ death. Importantly,
caregiver depression for those placing their loved ones in an
institution was slightly higher both pre- and post-death than for
those caring for the patient at home. These findings suggest
that interventions for caregiver support are particularly critical
in the periods immediately prior to and immediately after the
patient’s death.
The NIA’s REACH Project, a large, multi-site
intervention study of family caregivers of AD patients, was
designed to characterize and test promising interventions for
enhancing family caregiving. Nine different social and
behavioral interventions were tested, and investigators found that
the combined effect of certain interventions alleviated caregiver
burden, and that certain specific interventions, such as structured
family therapy, reduced depression. The second phase of the
study, REACH II, combines elements of the diverse interventions
tested in REACH into a single multi-component psychosocial
intervention and is ongoing.
Conclusion
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.
Data from the
Alzheimer’s Association. See also Ernst, RL; Hay,
JW. “The U.S. Economic and Social Costs of
Alzheimer’s Disease Revisited.” American Journal
of Public Health 1994; 84(8): 1261 – 1264. This study
cites figures based on 1991 data, which were updated in the
journal’s press release to 1994 figures.
Hebert, LE;
Scherr, PA; Bienias, JL; Bennett, DA; Evans, DA.
“Alzheimer Disease in the U.S. Population: Prevalence
Estimates Using the 2000 Census.” Archives of
Neurology August 2003; 60 (8): 1119 – 1122.
Data from the
Alzheimer’s Association. See also Evans, DA;
Funkenstein, HH; Albert, MS; et al. “Prevalence of
Alzheimer’s Disease in a Community Population of Older
Persons: Higher than Previously Reported.” JAMA
1989; 262(18): 2552 – 2556.
Lopez O, Jagust
WJ, DeKosky ST, Becker JT, et al. “Prevalence and
Classification of Mild Cognitive Impairment in the
Cardiovascular Health Study Cognition Study.”
Arch Neuro 60: 1385-1389, 2003.
Last Revised: March 24, 2004
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