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QUESTIONS SUBMITTED BY THE SUBCOMMITTEE

ALZHEIMER'S

Question. Last year the Committee provided a significant increase for Alzheimer's with funding for all of the several Institutes at NIH approaching $200 million total and almost $156 million at the National Institute on Aging. This is up from the $78 million the Institute spent on Alzheimer's in FY 1989 and the $91 million the Institute spent on Alzheimer's in FY 1990. In spite of these increases, I understand that the professional judgement of the Alzheimer's community is that the NIA budget for Alzheimer's should be set at $290 million in FY 1992.

Tell the Committee what we are learning about the causes and the possible cures for Alzheimer's. Do there continue to be scientific opportunities in the Alzheimer's field that should be pursued beyond the 1992 funding levels?

Answer. Research beyond that planned for FY 1992 could be pursued in many aspects of Alzheimer's disease research--basic biological studies into its etiology, means to improve upon early diagnosis, and the development of treatment approaches.

There are basically two approaches to the treatment of Alzheimer's disease. The first involves slowing, stopping, or reversing the biological processes that lead to the decreased functioning of nerve cells by compounds, such as nerve growth factor, that target the neurodegenerative process itself. Only very recently has information become available which indicates that we may be close to understanding some of the processes leading to cell death in Alzheimer's disease. Thus, it may take some time to develop compounds which are directed to these processes.

The other approach attempts to increase the functioning of Alzheimer's disease patients and ameliorate both the cognitive and non-cognitive behavioral symptoms. This may be through drugs or other compounds which facilitate the neural functioning of remaining neurons or which bypass the compromised systems, or by behavioral methods which help the patient use his or her available faculties to the fullest. NIA is encouraging and supporting the discovery, development, and testing of new pharmacological treatments and behavioral procedures directed toward relieving the symptoms of the disease and increasing the functioning of the patient.

One area in Alzheimer's disease treatment research to receive immediate emphasis would be preclinical drug studies. Once a potential drug is developed, it must be carefully tested under laboratory conditions, often using animal systems, to determine its efficacy before moving the drug to clinical trial studies in patients. Determination of toxicity after the biological activity of the compound has been assessed is also necessary. Toxicological tests must determine that there are not likely to be immediate or major deleterious effects on organ systems before the compound can be given to humans. The development of these resources would facilitate screening compounds in animal models

and would ensure that the development of new compounds for treating Alzheimer's disease would proceed to clinical testing as rapidly as possible.

Regarding research into the causes of Alzheimer' disease, it is characterized by neuropathological features known as amyloid plaques and neurofibrillary tangles: these are abnormal proteins and are the central lesions in the brains of Alzheimer's disease victims. A long-standing question has been whether the amyloid plaques and tangles represent causes or only parallel symptoms of some undetected disease process. We are now approaching the answer to this question.

Detailed studies of two families in which Alzheimer's disease is inherited has revealed a defect in the gene for the precursor of the amyloid protein. The significance of this result is that it is the first time any case of Alzheimer's disease has been traced to a cause. Although this exact defect probably does not cause the majority of Alzheimer's disease, the significance of these recent findings is that the amyloid plaques of Alzheimer's disease could represent the central causative event of the disease.

Another unanswered question in Alzheimer's disease is the cause of dysfunction and eventual death of neurons. This may be the most important issue, since it represents irreversible damage to the brain. Recently, amyloid beta protein was shown to have both growth-promoting and toxic effects on neurons in cell culture, depending on the developmental stage of the cells and the concentration of the protein.

With respect to the early diagnosis of Alzheimer's disease, the objective is to develop reliable multi-dimensional diagnostic procedures and instruments for identification. Advances would improve the correlation between clinical signs and the neuropathology discussed above and would allow patients, families, and physicians to know what they are dealing with and how to better plan for the future. Research has been funded on the use of non-invasive imaging techniques for diagnosis and is part of an overall effort to support the development and improvement of biological markers for diagnosis of Alzheimer's disease.

HEALTH AND RETIREMENT SURVEY

Question. Last year the Committee provided some additional funding and urged the NIA to continue planning for the Health and Retirement Survey. I understand that the planning phase of this survey is underway and that a cohort of Americans between the ages of 57 and 61 will be selected and tracked until their deaths to learn of changing trends in the older population. What important findings does the Institute expect to learn from this survey?

Answer. An award for a cooperative agreement was made in September 1990 to the University of Michigan to support the Health and Retirement Survey. The first year of the study includes an intensive planning phase, and the study is now five months into that phase. The first meeting of the monitoring committee was held March 5. The survey will likely focus on individuals who are initially between the ages of 51 (or 53) and 61. About 8,000 households will be included in the survey, yielding a sample of about 14,000 persons. The first interviews for this study are planned for April 1992.

This study will provide policy-makers and researchers with important and timely information concerning the role of key factors affecting the causes and consequences of retirement. Included in the study will be questions regarding health condition and disability status, work history, economic situation, pension policies, employer retirement incentives, family structure and family responsibilities. Researchers will be able to model the retirement decision-making process with data from this study. Much needed information focusing on the causes and consequences of retirement for women and minority groups will be collected as part of this study.

As findings emerge they will provide the necessary information base for federal and private sector retirement policies. They will assist in evaluating current policies aimed at allowing those who wish to continue working to have the maximum opportunity to do so. Retirement decisions can affect activities and financial resources for up to three decades beyond the date of retirement. The study will provide data on how people are making these decisions today in light of increased longevity and risk for long term disability.

Question. Could this same survey or study be conducted just as appropriately by the Agency for Health Care Policy and Research?

Answer. The focus of this study includes the role that health care plays on the decision to retire and the consequences of retirement for an individual and his or her family; however, the scope of this study encompasses numerous economic components in addition to health care. It is broader and different than the usual research supported by the Agency for Health Care Policy and Research, although any comments from the agency regarding the planning or implementation of the study would be welcomed. This study requires special expertise in areas such as retirement, public and private pensions, labor market behavior of older workers, savings for retirement, migration, housing, work-related disability, aging, and psychosocial characteristics of respondents.

The initial plans for the survey were fully discussed with other federal agencies and a special meeting of the Federal Forum on Aging-Related Statistics was held to discuss the survey; it was decided that NIA should conduct the study. Other federal agencies directly involved with planning the study and represented on the Health and Retirement Survey Monitoring Committee include the Social Security Administration, the National Center for Health Statistics, and the Office of Assistant Secretary for Planning and Evaluation, DHHS. Agencies providing technical assistance include the Health Care Finance Administration, the Pension and Welfare Agency and the National Institute for Occupational Safety and Health.

CANCER

Question. Dr. Williams, I understand that there are important connections between cancer and the aging process. And as you know the cancer incidence rate in older Americans, those over 65, is increasing. What can you tell us about the special problems of the elderly with regard to cancer, and what are the connections between cancer and the aging process?

Answer. Cancer is a major cause of disability and death in older people. Certain cancers, e.g. prostate, pancreatic and gliomas, are very rare in young persons but quite common in the older population, Recent studies using newer diagnostic techniques suggest that brain and prostate cancer are five times as common as previously thought. With respect to treatment, there is a reluctance to use therapeutically effective levels of chemotherapy in the older patient due to a concern that older people cannot safely tolerate the levels which have been shown to be effective in younger individuals; indeed, cancer exacerbates most other physical and mental disabilities. As persons age, the risk of cancer increases. Approximately 55 percent of all cancers occur in the age group 65 years or older; 66 percent of all cancer deaths occur in this age group. Because the aged segment of the population is expanding, a high potential exists for even more persons to be affected by cancer just in terms of sheer numbers.

It is not clear why cancer rates increase so rapidly with age. Multiple factors are thought to be involved, including the longer exposure to carcinogens, a decline in the body's ability to resist carcinogens and to repair DNA, and the immunodeficiencies which develop with aging. There is also a strong link between cellular senescence and cancer. At the cellular level, aging and cancer can be considered to be opposite sides of the same coin in the sense that the finite capacity of a differentiated cell to proliferate is both a cellular manifestation of organismal aging and a restraint to tumor progression. Gerontological research in this area has led to the identification of at least four genes in human cells which prevent uncontrolled proliferation of cells. Furthermore, it has been shown that the senescent cell produces proteins which inhibit the continued proliferation of tumor cells. Some biochemical processes known to be essential for cell proliferation have now been shown to be inhibited or absent in senescent cells, providing the first molecular glimpses of the altered cell proliferation machinery in senescent cells.

If we could manipulate this cell machinery in tumor cells in a similar way, we could then slow or even stop tumor progression.

Little research is currently directed toward cancer and aging, but it is an enormously important area in which much could be done. Animal studies have shown that reduction of total caloric intake greatly delays or even eliminates a variety of tumors in cancer prone animals. The NIA intramural research program is investigating tumor growth and metastasis in animals and has developed model systems which should aid in determining the basic mechanisms of tumor growth of specific age-onset cancers. In addition, a recent collaborativė study, tapping the unique resources of the Baltimore Longitudinal Study of Aging (BLSA)--a bank of biological samples and comprehensive

longitudinal health data--has demonstrated that long term trends in prostate specific antigen may be useful as an early marker of prostate cancer, There are comparable opportunities to conduct "instantaneous BLSA longitudinal studies" of markers for certain other cancers (breast, colon) which, if successful, may allow early detection and prevention. The stage has been set for a major new NIA intramural initiative on cancer and aging to be pursued.

Data on the influence of aging on cancer patient management are limited. The NIA is particularly interested in promoting research to further the understanding of relationships between the processes of aging and cancer at the level of the organ system for the tumors that most heavily afflict older-aged persons, such as cancers of the prostate, breast, colon, rectum, ovary, and urinary bladder. For some malignancies, older-aged persons are more likely to be initially diagnosed with a later stage of disease than younger persons. Older-aged persons are also likely to have concomitant chronic diseases and/or disabling conditions in conjunction with the diagnosis of cancer that may present clinicians with unique treatment situations such as potential for drug-drug interactions and masked features of adverse conditions. Knowledge derived from the studies of younger patients with cancer may not be generalizable to older-aged individuals' needs because of any number of complicating age-related factors. Behavioral issues in cancer screening and early detection also warrant special consideration for older people. For example, older women are less likely than younger women to perform breast self exams although they are at higher risk of cancer. NIA initiatives related to behavioral and psychosocial aspects of cancer and aging include the July 1990 Forum on Breast Cancer Screening for Older Women and a forthcoming workshop on older-aged cancer survivors.

Researchers and clinicians working in the areas of aging and cancer are confronting the many challenges and complexities of interrelationships between problems of old age and cancer. The burgeoning growth of the older-aged segment of the population, the intensity of health care resources used by older individuals, the lack of information specific to the natural history of tumors in the aged, and the effects of prevention and treatment practices on the older-age person with cancer combine to create an urgent need for a special focus on aging and cancer. Therefore, the NIA is committed to developing new information in clinical medicine and in the basic sciences applicable to the aging/cancer interface. This past year, a senior position was established in the NIA to provide additional liaison and consultation on the relationship between aging and cancer, and to address the urgency and national interests in this area. This position provides for the liaison with the National Cancer Institute (NCI), other federal agencies, and organizations in the private sector such as the American Cancer Society and the Association of American Cancer Institutes to promote research and other activities (information transfer) in such diverse scientific areas as geriatric medicine, oncology, biology, and epidemiology. The NIA and NCI staff are currently working together to sponsor activities such as conferences and workshops to promote high quality research on the many Interactions between cancer and aging.

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