Apolipoprotein E epsilon4 allele and familial aggregation of Alzheimer disease.

Abstract

To investigate the relationship among risk for Alzheimer disease (AD), familial aggregation of AD, and the apolipoprotein E (apoE) epsilon4 allele in first-degree relatives of probands with AD and known apoE genotype. Two hundred ninety subjects fulfilling the criteria of the National Institute of Neurological Communicative Disease 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. Family data were collected on 1176 first-degree relatives (parents and siblings), aged 40 to 90 years. Most living relatives underwent a clinical examination, whereas we relied on family history for clinical data for deceased or unavailable relatives. First, we 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 epsilon4 allele by deriving the expected proportions of relatives with 0, 1, or 2 apoE epsilon4 alleles conditionally on the proband's genotype. Cumulative LTR for AD among first-degree relatives increased significantly with the number of epsilon4 alleles present in the proband. By 90 years of age, LTRs in relatives of probands with epsilon3/epsilon3, epsilon3/epsilon4, and epsilon4/epsilon4 genotypes were 29.2%, 46.1%, and 61.4%, respectively. Significant sex-by-apoE genotype interaction effects on LTR were observed. Women had about a 2-fold higher risk for AD than men among relatives of epsilon4 carriers but not among relatives of non-epsilon4 carriers. The predicted proportion of epsilon4 carriers in relatives of probands with epsilon3/epsilon3 genotype remains about 50% lower than the corresponding LTR for AD, indicating that familial clustering of AD is largely due to other factors than the apoE epsilon4 allele. Although aggregation of AD in families of probands with the epsilon4 allele is more prominent, we estimated that AD would not develop in about 30% of female and up to 60% of male relatives carrying at least 1 epsilon4 allele, even by 90 years of age. Our results support the hypothesis that the apoE epsilon4 allele enhances AD susceptibility, but putative factors enhancing risk for AD remain to be found.