APOLIPOPROTEIN-E EPSILON-4 ALLELE AND FAMILIAL AGGREGATION OF ALZHEIMER-DISEASE

Objective: To investigate the relationship among risk for Alzheimer di sease (AD), familial aggregation of AD, and the apolipoprotein E (apoE ) epsilon 4 allele in first-degree relatives of probands with AD and k nown apoE genotype. Patients: Two hundred ninety subjects fulfilling t he criteria of the National Institute of Neurological Communicative Di sease and Stroke-Alzheimer's Disease and Related Disorders Association for probable AD were ascertained from March 1, 1992, to December 31, 1996, through consecutive admissions in several university hospitals. Design and Methods: Family data were collected on 1176 first-degree re latives (parents and siblings), aged 40 to 90 years. Most living relat ives underwent a clinical examination, whereas we relied on family his tory for clinical data for deceased or unavailable relatives. First, w e conducted standard survival analyses to estimate cumulative lifetime risk (LTR) for AD among relatives and to investigate for sex and apoE genotype effects on LTR. Then, we assessed to what extent clustering of secondary AD could be explained by the apoE epsilon 4 allele by der iving the expected proportions of relatives with 0, 1, or 2 apoE epsil on 4 alleles conditionally on the proband's genotype. Results: Cumulat ive LTR for AD among first-degree relatives increased significantly wi th the number of epsilon 4 alleles present in the proband. By 90 years of age, LTRs in relatives of probands with epsilon 3/epsilon 3, epsil on 3/epsilon 4, and epsilon 4/epsilon 4 genotypes were 29.2%, 46.1%, a nd 61.4%, respectively. Significant sex-by-apoE genotype interaction e ffects on LTR were observed. Women had about a 2-fold higher risk for AD than men among relatives of epsilon 4 carriers but not among relati ves of non-epsilon 4 carriers. The predicted proportion of epsilon 4 c arriers in relatives of probands with epsilon 3/epsilon 3 genotype rem ains about 50% lower than the corresponding LTR for AD, indicating tha t familial clustering of AD is largely due to other factors than the a poE epsilon 4 allele. Although aggregation of AD in families of proban ds with the epsilon 4 allele is more prominent, we estimated that AD w ould not develop in about 30% of female and up to 60% of male relative s carrying at least 1 epsilon 4 allele, even by 90 years of age. Concl usion: Our results support the hypothesis that the apoE epsilon 4 alle le enhances AD susceptibility, but putative factors enhancing risk for AD remain to be found.