Vo). 19, No. 1 Printed In USA.
Genetic Epidemiology of Alzheimer Disease
Arjen J.C. Slooter and Cornelia M. van Duijn
Dementia is a major health problem in the elderly. Following an extended period of loss of personality and cognition, thedisease results in a state of complete dependency. By far the most common cause of dementia is Alzheimer disease, which is clinically characterized by a gradual, progressive decline in intellectual functions (1). Psychosis, depression, agitation, and anxiety are common manifestations (2). The most frequently used diagnostic criteria for Alzheimer disease are described by the National Institute ofNeurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) (3). The diagnosis of Alzheimer disease is considered to be probable when alternative causes of dementia are excluded (3, 4). According to the NINCDS-ADRDA criteria, a definite diagnosis is made when a probable diagnosis of Alzheimer disease is confirmed at autopsy (3). Theneuropathologic characteristics of Alzheimer disease are senile plaques, neurofibrillary tangles, amyloid angiopathy, neuronal loss, as well as decreased activity of the enzyme choline acetyltransferase (5). Senile plaques are extracellular deposits of predominantly /3-amyloid. Neurofibrillary tangles are intraneuronal inclusions, which are, in part, composed of abnormally phosphorylated tauprotein. The prevalence of Alzheimer disease increases with advancing age. It affects less than 1 percent of individuals aged 60-64 years, and up to 40 percent of those over age 85 years (6). Also, the incidence increases with aging, and is estimated to be 1 per 1,000
Received for publication December 27, 1996, and accepted for publication July 22, 1997. Abbreviations: ACT, o^-antichymotrypsln gene;AP0E, apollpoprotein E gene; APP, amyloid precursor protein gene; NACP, gene for non-amyloid-p component of amyloid precursor protein; NINCDS-ADRDA, Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association; PS-1, presenilin 1 gene; PS-2, presenilin 2 gene; VLDL-r, gene for very low density lipoprotein receptor. From the Department ofEpidemiology and Blostatistics, Erasmus University Medical School, Rotterdam, The Netherlands. Reprint requests to Dr. A. J. C. Slooter, Department of Epidemiology and Btostatistics, Erasmus University Medical School, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
person-years in individuals aged 60-64 years and 25 per 1,000 person-years in individuals older than 85 years (7). In Alzheimerdisease research, patients with early-onset are often distinguished from those with late-onset. There is, however, no uniform definition, and frequently used cut-off points are the ages of 60, 65, and 70 years. Besides age, previous head injury, depression, low educational level, atherosclerosis, and exposure to aluminum were found to be risk factors (7-9). The use of anti-inflammatory drugs orestrogens seems to decrease the risk of Alzheimer disease (7, 10). Smokers were also found to have a decreased risk in cross-sectional studies (11), but at an increased risk in a follow-up study (12). Genetic factors play a role in the etiology of Alzheimer disease. Familial clustering has long been recognized (13), and a positive family history of dementia is one of the most consistent risk factors(14). A distinction is often made between patients with familial and sporadic Alzheimer disease. Again, there is no uniform definition of these forms of the disease. The frequently used criterion of a positive family history of dementia does not necessarily indicate genetic susceptibility. Many people in a family, and not just those individuals who are genetically predisposed, develop Alzheimer...