It will be reviewed this sections, “Alzheimer Disease,” and “The Molecular and Genetic Basis of Alzheimer Disease,” as will the amyloid cascade hypothesis of Alzheimer disease, the possible neurotoxicity of amyloid beta oligomers (Walsh and Selkoe 2007), and the major risk factor for late-onset Alzheimer disease- the inheritance of the e 4 allele of the choleresterol- transporting protein apolipoprotein E (Corder et al. 1993)- and its possible relationship to the formation of neurofibrillary tangles.

Robert Katzman’s (1976) editorial in the Archives of Neurology pointing out the prevalence of Alzheimer disease and its impact on life span is widely credited for sparking Alzheimer disease research in the United States (Khachaturian 2006). Congress had authorized creation of the National Institute on Aging (NIA) in 1974. By 1976, the institute was formally organized under the direction of psychiatrist Robert Butler (Figure 1-6), and in 1978, it began its program of extramural research on brain aging and Alzheimer disease under the leadership of Zaven Khachaturian (Figure 1-7). In 1979, the Alzheimer’s Association (first named the Alzheimer’s Disease and Related Disorders Association; ADRDA) was formed with encouragement and support from the NIA and the National Institute of Neurological and Communication Disorders and Stroke (NINCDS); Mr. Jerome Stone became President, and Drs. Robert Katzman and Carl Eisdorfer cochaired the Medical Advisory Board (Alzheimer’s Association 2008).

The year 1981 saw the publication of a government industry-academia collaboration titled Strategies for the Development of an Effective Treatment for Senile Dementia (Crook and Gershon 1981) that stimulated some of the early U.S. drug trials. The title of the follow-up volume, Treatment Development Strategies for Alzheimer’s Disease (Crook et al. 1986), indicated the recognition that senile dementia and Alzheimer disease were the same pathological entity. Between these two publications, on the advice of the NINCDS National Advisory Council, NINCDS and ADRDA formed the Work Group on the Diagnosis of Alzheimer’s Disease to establish clinical diagnostic criteria so that the natural history of the disease could be better characterized and meaningful clinical trials undertaken. The diagnostic criteria that were formulated for possible and probable Alzheimer disease (McKhann et al. 1984) continue in use as the basis for enrollment in clinical trials.

FIGURE 1-7.  Zaven Khachaturian, M.D., first associate director of the Neuroscience and Neuropsychology of Aging Program of the National Institute on Aging.
Source.  Courtesy of Dr. Khachaturian.

Morris and Rubin (1991) reported that these criteria have 80%-90% accuracy. A recent review of autopsy cases (Ranginwala et al. 2007) finds this accuracy rate essentially unchanged despite advances in immunohistochemistry that now enable more ready detection of Lewy bodies and tauopathies other than the neurofibrillary tangles of Alzheimer disease.

In 1986, a grant from NIA enabled the creation of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) to standardize the clinical, neuropsychological, and neuropathological evaluation of persons with suspected Alzheimer disease. In this effort, led by Dr. Albert Heyman of Duke University, patients with Alzheimer disease and control subjects without dementia were recruited from 24 NIA-sponsored Alzheimer’s disease centers and from other university programs in the United States. Subjects were examined at entry and annually thereafter, to observe the natural progression of Alzheimer disease. Autopsy examination of the brain was included, to the extent possible. The major standardized instruments developed by CERAD are now used by many Alzheimer disease research centers in the United States and abroad, by physicians in clinical practice, and in population-based surveys. Data were obtained on more than 1,000 nationally distributed white and black patients with Alzheimer disease and nearly 500 control subjects without dementia. In this series, the clinical diagnosis of Alzheimer disease based on NINCDS-ADRDA criteria was confirmed in 87% of autopsied cases. The CERAD database is still available to investigators.

In 1991, the Alzheimer’s Disease Cooperative Study was funded by NIA under the direction of the late Leon Thal (Figure 1-8) to provide an infrastructure for clinical trials of substances that have included estrogen and nonsteroidal anti-inflammatory agents.

Most recently (2004), the Alzheimer’s Disease Neuroimaging Initiative was established with resources from the National Institute on Aging, the National Institute for Biomedical Imaging and Bioengineering, the Foundation for the National Institutes of Health, the Alzheimer’s Drug Discovery Foundation, and the Alzheimer’s Association to examine how brain imaging technology can be used with other biological marker tests to measure the progression of mild cognitive impairment and early Alzheimer disease. This information will then be used to aid future clinical trials by providing a standard assessment tool to measure treatment effects (Mueller et al. 2005).

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Myron F. Weiner, M.D.
Clinical Professor of Psychiatry and Neurology,
Aradine S. Ard Chair in Brain Science,
Dorothy L. and John P. Harbin Chair in Alzheimer’s Disease Research,
University of Texas Southwestern Medical Center at Dallas, Texas
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