DHHS Eagle graphic
ASL Header
Mission Nav Button Division Nav Button Grants Nav Button Testimony Nav Button Other Links Nav Button ASL Home Nav Button
US Capitol Building
HHS Home
Contact Us
dot graphic Testimony bar

This is an archive page. The links are no longer being updated.

Testimony on Meeting the Challenges of Alzheimer's Disease: The Biomedical Research That Will Carry Us into the 21st Century by Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
U.S. Department of Health and Human Services

Before the Senate Labor and Human Resources Committee, Subcommittee on Aging
June 5, 1997

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.

Privacy Notice (www.hhs.gov/Privacy.html) | FOIA (www.hhs.gov/foia/) | What's New (www.hhs.gov/about/index.html#topiclist) | FAQs (answers.hhs.gov) | Reading Room (www.hhs.gov/read/) | Site Info (www.hhs.gov/SiteMap.html)