Chairman Gregg and Members of the Senate Labor and Human Resources
Subcommittee on Aging, we are engaged in a remarkable period Of Alzheimer's
disease discovery. Not long ago, "senility" was thought to be an inevitable
consequence of aging, but research has since proved that, without disease, the
human brain continues to function well throughout life.
Dementia, or the loss of intellectual function, results from disease, and
Alzheimer's disease is the most common cause of dementia in older people.
Tragically, an estimated four million people now suffer from Alzheimer's
disease, a progressive brain disorder marked by an irreversible decline in
intellectual abilities and by changes in behavior and personality. Alzheimer's
disease devastates its victims. Although the early signs involve mild
forgetfulness, the dementia ultimately leaves patients incapable of caring' for
themselves. Behavior changes may cause patients to become agitated, sometimes to
the point of causing harm to themselves or others. As a result, Alzheimer's
disease has a profound effect on the millions of family members and other loved
ones who provide most of the care for people with this disease.
Because the prevalence of Alzheimer's disease doubles every five years
beyond age 65, the rapid growth of the oldest old population is expected to
place a significantly greater number of people at risk for the disease. Some
scientists have projected a tripling of Alzheimer's disease patients by the year
2050 to 14 million individuals. It is urgent that we define the causes and
features of Alzheimer's disease and find ways to combat it.
Fortunately, as understanding of the disease grows, so do the opportunities
for developing interventions to halt or slow its progress. The National
Institute on Aging (NIA) leads a national effort, in collaboration with several
components of the National Institutes of Health and other agencies, to conquer
this devastating disease by working to understand the biological mechanisms
underlying Alzheimer's disease, to develop treatments and cures based on
research findings, and eventually to discover ways to prevent the disease.
Pathological signs. When Dr. Alois Alzheimer studied the pathology of this
dementia in 1907, he described two distinctive features in the brain that still
characterize in the disease. The first feature is the plaque, composed largely
of a protein fragment called beta-amyloid, normally secreted by brain cells.
Plaques gradually accumulate in the spaces between nerve cells in the brains of
patients with Alzheimer's disease. Many scientists believe that beta-amyloid
contributes to the nerve cell death that leads to dementia in Alzheimer's
disease.
The other feature is the neurofibrillary tangle, which is composed mainly of
an abnormal form of a protein called tau. Normally, tau supports the
microtubular structure that transports molecules within nerve cells. In
Alzheimer's disease, however, abnormal tau accumulates to form tangles inside
nerve cells, disrupting cell functions. Scientists also believe that tangles
could cause cell injury and death as they build up inside cells.
While some plaques and tangles occur with normal aging, they are much more
numerous in persons with Alzheimer's disease. A significant amount of research
is devoted to understanding the origin of plaques and tangles in Alzheimer's
disease and to learning how they relate to nerve cell death, loss of neuronal
connections, and other features, such as inflammation, also seen in the brains
of Alzheimer's disease patients. Scientists hope to translate this knowledge
into therapies that will slow or prevent the progress of Alzheimer's disease.
For many decades after Dr. Alzheimer described plaques and tangles, these
features were not commonly associated with the dementia of old age, which was
widely believed to be an 'inevitable consequence of aging. This belief has
largely been dispelled by a broad scientific initiative to understand the
disease. Researchers have recognized different forms of Alzheimer's disease. In
some individuals, symptoms occur in persons as young as 30 years. This rare,
early-onset form of Alzheimer's disease occurs in a small number of individuals
and accounts for approximately 10 percent of cases of Alzheimer's disease. The
common, late-onset form of Alzheimer's disease, in which symptoms appear after
age 65, accounts for approximately 90 percent of cases.
Genetic links. Beginning in 1990, research has produced a remarkable series
of genetic discoveries. Researchers identified mutations in three genes that
cause the familial, early-onset form of the disease, and identified a fourth
gene that is a risk factor for the common, late-onset form of the disease. The
first early-onset gene mutation discovered, on chromosome 21, is in the gene
that codes for the parent protein of the beta-amyloid peptide found in plaques.
Mutations were soon found in genes on chromosomes 14 and 1, associated with
early-onset Alzheimer's disease. Mutations in the chromosome 14 gene are the
most common, being responsible for 40 to 50 percent of early-onset cases
inherited in families. In these early onset cases, inheritance of just one copy
of the mutated gene causes the disease. In addition, there remain some familial,
early-onset Alzheimer's disease cases not caused by mutations in any of the
known genes, making it likely that there are more genes still to be identified.
The fourth gene, associated with the more common form of Alzheimer's disease
in which symptoms occur in later years, was found on chromosome 19. Knowing that
there were families in which many members developed Alzheimer's disease late in
life, researchers looked for a genetic link. The search led to a gene that codes
for forms (alleles) of the protein apolipoprotein E (ApoE). One of the forms,
ApoE4, is now recognized as the first genetic risk factor identified for the
common, late-onset form of Alzheimer's disease. Epistemological studies have
suggested that the age of onset of Alzheimer's disease can vary by as much as 20
years depending on whether a person inherits no copies, one copy, or two copies
of ApoE4. Recent research findings support the possibility that development of
at least some cases of late-onset Alzheimer's disease involves other risk factor
genes, and investigators are pursuing the location of these genes on other
chromosomes, as well as their identification.
To aid in analyzing the disease process in the different forms of
Alzheimer's disease, researchers last year genetically engineered a transgemic
mouse. The mouse carries mutated human genes associated with Alzheimer's
disease. This is the first animal model to exhibit some of the cognitive as well
as the neuropathological features of Alzheimer's disease. This model provides an
important research tool for understanding Alzheimer's disease and for expediting
the testing of potential Alzheimer's disease drug therapies.
Ethical issues. A degenerative disease such as Alzheimer's disease raises
important ethical questions regarding care, genetic testing, and research.
Considerable attention has been given to the ethics of elective genetic testing
for Alzheimer's disease, apart from research purposes. Predictive testing is
possible 'in the autosomal dominant genes linked to early-onset families. The
ApoE allele, however, is not absolutely predictive of Alzheimer's disease in
asymptoniatic individuals. To date, there is a consensus among most researchers,
policy experts, ethicists, and others, that except for autosomal dominant early-
onset families, Alzheimer's disease genetic testing should not be used for
screening or diagnosis in asymptomatic individuals. Genetic testing is
currently a particular concern given the potential for employment and insurance
discrimination.
Issues of informed consent, both for health care and for participation in
research, are of particular concern for Alzheimer's disease patients and others
with diminished cognitive abilities. Special efforts are being made to improve
the consent process for care, to encourage advance care planning while the
patient is able, and to make the consent process meaningful to potential
participants in Alzheimer's disease intervention studies.
Potential for early detection. The genetic involvement of Alzheimer's
disease offers a number of opportunities for discovering disease mechanisms,
improving diagnostic tests, and identifying targets for treatment. For example,
scientists recently studied the cognitive and brain function of volunteers aged
50 to 64 years to compare those having two copies of the ApoE4 allele (who are
at high risk for developing Alzheimer disease) with controls having no ApoE4
allele. Although neuropsychological tests found all volunteers to be cognitively
normal, brain imaging technology showed that an increased proportion of
individuals with two ApoE4 alleles had reduced glucose metabolism in the same
areas of the brain as patients with probable Alzheimer's disease. These findings
indicate that it may be possible to identify brain function abnormalities in
persons with no clinical symptoms who are at high risk for Alzheimer's disease
many years before they would be expected to develop such symptoms. This provides
opportunities for the development of early interventions that would delay or
prevent the brain damage seen in fully developed Alzheimer's disease. Stopping
or delaying the progression of the disease prior to onset of noticeable symptoms
would make a major contribution to quality of life and continued function.
Early recognition and appropriate assessment of Alzheimer's disease are
critical goals. Family members, especially spouses, can be instrumental in
interpreting early signs and symptoms and seeking evaluation and treatment. A
study of Japanese-American men and their families in Hawaii, however, found that
many wives and other family members had not recognized or reported memory
problems in individuals with mild to more severe dementia. Further, more than
half of the individuals with recognized memory problems had not received a
dementia evaluation. These results highlight the importance of public education
efforts to improve recognition and reporting of symptoms very early in the
illness in order to take advantage of 'interventions for 'individuals with
potentially treatable dementias, and to help patients and families plan for the
future.
Epidemiologic research. While determining the prevalence of Alzheimer's
disease in the United States is important for health policy formulation and
research planning, differing Alzheimer's disease prevalence estimates generated
by studies in various populations provide key evidence suggesting potential risk
factors (both genetic and environmental) as well as protective factors.
Epidemiologic studies, particularly those comparing different populations,
provide crucial clues to these factors, as well as to the causes of and
potential treatments for Alzheimer's disease. Triggered by clues from basic
research, epidemiologic studies have been very effective, for example, in
helping to identify genetic and environmental risk and protective factors for
Alzheimer's disease. As a result of epidemiologic research, age, a history of
severe head trauma, and coexisting medical conditions, such as vascular disease,
are now viewed as potential Alzheimer's disease risk factors. In contrast, high
levels of education and cognitive ability have been linked to lower risk for
developing Alzheimer's disease in late life.
Epidemiologic studies have also suggested that estrogen replacement therapy,
use of non-steroidal anti-inflammatory drugs, and use of anti-oxidants are
protective against Alzheimer's disease. One such study provided the strongest
evidence to date that taking estrogen after menopause may delay the onset and
reduce the risk of Alzheimer's disease in postmenopausal women. In this study,
16.3 percent of the women who had not used estrogen developed Alzheimer's
disease, while only 5.8 percent of the women who had taken estrogen developed
the disorder. Recent results of a 15-year study found that anti- inflammatory
drugs such as ibuprofen, taken for as little as two years, also appear to reduce
the risk of Alzheimer's disease. In most forms of Alzheimer's disease,
therefore, disease progress may be influenced by multiple factors.
Coexisting vascular disease. We are also learning more about the
relationship of AD to other conditions affecting older persons. In a recent
finding that described the coexistence of Alzheimer's disease with vascular
disease in elderly U.S. nuns, the presence of small strokes in parts of the
brain below the cortex resulted in more severe dementia than expected on the
basis of Alzheimer's disease neuropathology alone. In comparison, people with
such small strokes in any brain region in the absence of Alzheimer's disease
neuropathology generally had no significant changes in cognitive function when
compared with controls. Approximately half of the demented patients 'in this
autopsy study had these small strokes. These results strongly suggest that
prevention or treatment of vascular disease could delay or reduce the
development of symptoms in many Alzheimer's disease patients.
Clinical studies. In order to speed the discovery, development, and testing
of new compounds to treat Alzheimer's disease, the NIA complements its broad
basic research efforts with strategies that encourage the translation of basic
research findings to the development of interventions to be tested in clinical
studies. NM's Drug Discovery Groups represent an innovative approach to
fostering this process. These research teams are expanding the range of
pharmacologic and behavioral approaches to the treatment of Alzheimer's disease
and exploring the development of novel delivery systems to the brain.
NIA's Alzheimer's Disease Cooperative Study (ADCS) coordinates the efforts
of 35 institutions to rapidly respond to ideas for potential treatments by
conducting clinical studies for the treatment of cognitive impairment and
behavioral disorders associated with Alzheimer's disease. The design of this
consortium makes it possible to conduct multiple clinical studies simultaneously
in response to rapidly-emerging scientific opportunities. Evidence from basic
and epidemiologic research has stimulated clinical studies of anti-oxidants,
anti-oxidant inflammatory agents, and estrogen to explore ways of slowing the
degenerative progress of Alzheimer's disease. A recently completed clinical
trial, conducted by the ADCS, assessed the effectiveness of selegiline (an
anti-oxidant drug used in Parkinson's disease) and vitamin E (an anti-oxidant
vitamin), both separately and in combination, in delaying the progression of
Alzheimer's disease. This trial showed that selegiline and vitamin E may slow
development of functional signs and symptoms of Alzheimer's disease by about
seven months. Each of the two drugs delayed important milestones for people with
moderately severe Alzheimer's disease, such as entry into nursing homes and loss
of ability to perform activities of daily living. Delays in the onset of ever
more troubling symptoms are viewed by caregivers as an important step.
The ADCS is now studying the effects of other promising therapies, including
the steroidal anti-inflammatory agent prednisone; the efficacy of estrogen
replacement therapy in women with mild to moderate Alzheimer's disease; and the
impact of psychoactive drugs and behavior management techniques o reducing
disruptive, agitated behavior in Alzheimer's disease patients.
In addition, a large NIH randomized trial of hormonal replacement, the
Women's Health Initiative, is being used to test the ability of hormonal
replacement to prevent cognitive decline.
Caregiving. The prolonged and intense caregiving of Alzheimer's disease
patients affects the physical, mental, and social health of the caregiver.
Fatigue, insomnia, and other physical symptoms are frequent. Depression is not
uncommon. Cardiovascular risk factors, such as high blood pressure, may be
affected. In response, scientists are testing various methods to help family
members who care for people with Alzheimer's disease. Strategies are being
developed to 'increase the caregiver's emotional support, improve services that
ease the burden for caregivers, and provide knowledge and skills training useful
for coping with the symptoms of Alzheimer's disease.
Families find decisions surrounding placement in a nursing home extremely
difficult. Research is helping to define whether and when to turn to a nursing
home, and to evaluate what type of care is best for the patient. Additional
studies are identifying the strategies that promote the most effective, highest
quality institutional care.
Future research. Alzheimer's disease is a devastating condition that rumis
the lives of those who have the disease and disrupts the lives of their
caregivers. Over the last five years, research has resulted in major advances in
our understanding of the disease, including the discovery of genetic components,
detection of risk factors, and identification of potential protective
interventions. As the pace of research accelerates, new findings will make
possible better understanding of factors contributing to nerve cell death and
will improve our ability to predict who is at risk for developing Alzheimer's
disease. We are at the threshold of further discoveries that will lead to more
accurate methods of diagnosis, and to the development of more effective
treatments and preventive interventions to reduce the scourge of Alzheimer's
disease.
