ABSTRACT
Familial aggregation of Alzheimer’s disease (AD) has been recognized since the earliest formal descriptions of this disease. The degree to which genetic risk factors play a role in the pathogenesis of AD however has been less clear. In the past several years, a number of genetic epidemiology studies have been undertaken on probands with AD and their families (Heyman et al., 1984; Rocca et al., 1986; Breitner et al., 1988; Farrer et al., 1991; Bergem et al., 1992; Katzman and Kawas, 1994; Lautenschlager et al., 1996). Cumulatively, these studies (for review see, Katzman and Kawas, 1994) strongly argue that the familial aggregation of AD is not due simply to the high frequency of AD in the general population. These studies suggest that the age-dependent risk and the overall lifetime risk for AD in first-degree relatives of AD probands varies from 10-50%. The most comprehensive recent study suggests an age-dependent risk curve asymptotic to a final risk of 38% by age 85 years (Lautenschlager et al., 1996). The latter study, as well as several other earlier epidemiologic studies make it difficult to assign a pure Mendelian mode of transmission in the majority of AD cases. Instead, these studies and also studies of individual pedigrees imply that the majority of cases of familially aggregated AD probably reflect a complex mode of transmission such as a common but incompletelypenetrant single autosomal gene defect, a multi-genic trait, or more probably a mode of transmission in which genetic and environmental factors interact. Nevertheless, there is a small proportion of AD cases which appear to be transmitted as a pure autosomal dominant Mendelian trait with age-dependent penetrance (for review see, St George-Hyslop et al., 1987). Analysis of these pedigrees with molecular genetic tools has provided several powerful insights into the pathogenesis of AD.
