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The ideal biomarker for Alzheimer's disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases: it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias: it should be reliable, reproducible non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD. it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Aβ 42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD. these measures are not useful. but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD. cerebrospinal fluid assays showing low levels of Aβ 42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.

The U.S. Senate Committee for Appropriations (for the Departments of Labor, Health and Human Services, and Education and Related Agencies), in its report of the fiscal year 1994 appropriations bill, directed the National Institute on Aging (NIA) to develop a long-range plan for taking advantage of scientific opportunities in Alzheimer's disease (AD) research.

Even though the prospect for preventing Alzheimer disease seems remote now, a plan must be developed to reach this goal in order to avoid a fiscal crisis in the health care system. The goals of delaying Alzheimer disease and eventually preventing it will become possible as more is learned about the brain mechanisms and risk factors involved. In response to a 1994 Congressional report, the National Institute on Aging in cooperation with the Zachary and Elizabeth M. Fisher Medical Foundation sponsored a workshop to address potential strategies for the prevention of Alzheimer disease. The workshop helped to identify the necessary resources and the types of technical problems involved in developing methods to prevent Alzheimer disease. This volume presents the position papers which served as the springboard for the discussions at the workshop, out of which developed a number of specific recommendations including new epidemiological studies for well defined population groups, identification of high risk populations for treatment and prevention studies, and coupling of new questions and add-on investigations to in-progress studies.

Falls are a serious health risk for older adults. But for those living in rural and frontier areas of the USA, the risks are higher because of limited access to health care providers and resources. This study employed a community-based participatory research approach to develop a fall prevention toolkit to be used by residents of rural and frontier areas without the assistance of health care providers. Qualitative data were gathered from both key informant interviews and focus groups with a broad range of participants. Data analysis revealed that to be effective and accepted, the toolkit should be not only evidence based but also practical, low-cost, self-explanatory, and usable without the assistance of a health care provider. Materials must be engaging, visually interesting, empowering, sensitive to reading level, and appropriate for low-vision users. These findings should be useful to other researchers developing education and awareness materials for older adults in rural areas.

Introduction A Synthesis of Critical Topics in Alzheimer's Disease, Z.S. Khachaturian and T.S. Radebaugh Overview and Historic Perspectives Current Research on Alzheimer's Disease in an Historical Perspective, R. Katzman A History of the Morphology of Alzheimer's Disease, R.D. Terry Epidemiology Putative Risk Factors for Alzheimer's Disease, R. Mayeux Descriptive Epidemiology of Alzheimer's Disease, D.A. Evans Methods of Screening for Survey Research on Alzheimer's Disease and Related Dementias, B.J. Gurland Diagnosis Differential Diagnosis of Alzheimer's Disease, J.C. Morris Clinical Assessment of Patient with Dementia, S. Gilman Heterogeneity of Alzheimer's Disease, A. Heyman The Use of Tests and Instruments in the Evaluation of Patients with Dementia, R.C. Mohs Biological Markers The Neuropathology of Alzheimer's Disease: Diagnostic Features and Standardization, S.S. Mirra and W.R. Markesbery Pathology, Neurobiology, and Animal Models of Alzheimer's Disease, J.C. Troncoso, B.J. Crain, S.S. Sisodia, and D.L. Price Neuroimaging Applications for the Study of Alzheimer's Disease, T.F. Budinger Cause(s) Intrinsic Biological Aging as Underlying Pathogenetic Mechanism, G.M. Martin Cerebral Metabolic Impairments, J.P. Blass The Metabolism of Apolipoprotein E and the Alzheimer's Diseases, A.D. Roses Neuroimmune Mechanisms in the Pathogenesis of Alzheimer's Disease, P.L. McGeer and E.G. McGeer Causes of Alzheimer's Disease, A.B. Young Trace Elements in Alzheimer's Disease, W.R. Markesbery Treatment Clinical Drug Trials in Alzheimer's Disease: Methodological Considerations, L.J. Thal Pharmacological Approaches to Behavioral Symptoms in Alzheimer's Disease, D. Galasko Treatment of Alzheimer's Disease, L. Shihabuddin and K.L. Davis Psychosocial Interventions, M.S. Mittelman and S.H. Ferris Care and Management Inappropriate Behavior, J. Cohen-Mansfield Managing Problems in Dementia Patients: Depression and Agitation, L. Teri Overview of Psychosocial Factors Contributing to Stress of Family Caregivers, K.C. Buckwalter The Influence of Social Context on the Caregiving Experience, R.J.V. Montgomery Care for Families Facing Alzheimer's Disease: Primary Care Practice Implications from Research, L.P. Gwyther Index

Summary: A fundamental problem in research aimed at developing and testing new treatments for Alzheimer disease (AD) is determing drug efficacy. At the present time, while there are no biological markers for diagnosing or assessing this disease, investigators must rely on clinical judgment and neuropsychological outcome measures to determine if and when a new treatment may be beneficial. The following article provides an overview of the issues involved in conducting a clinical trial in AD when measures of cognitive and behavioral changes are used. It is based on the proceedings from an international workshop on this topic that was convened by the National Institute on Aging in January 1990

Dr. Khachaturian highlighted the importance of noncognitive symptoms of Alzheimer's disease (AD) for the care providers versus our current lack of knowledge about these symptoms' origin, their relationship with cognitive loss, and our ability to control them. Our relatively greater understanding of the pathophysiology of cognitive loss is not yet matched with respect to non-cognitive symptoms, explaining the hit-and-miss treatment approaches currently in use. It is thus essential to study the underlying biological basis of noncognitive changes in AD. Nonpharmacological approaches to the management of noncognitive symptoms in later stages of AD such as teaching of coping strategies must be encouraged, because they may have a major impact on the patient and the care providers. There is a relative paucity of instruments and clear outcome variables for noncognitive symptoms, including quality of life, which will have to be defined as related to the patient or to caregivers. Such symptoms should be studied in a holistic way in order to treat the underlying pathophysiological process rather than just suppressing unacceptable behaviors such as agitation. Although noncognitive symptoms in later stages of AD are important, from a national research strategy perspective, priority should be given to delaying onset of symptoms by some 10 years. Humane and ethical considerations must always predominate in research on treatment for later stages of AD.