GENDER DIFFERENCE IN APOLIPOPROTEIN E-ASSOCIATED RISK FOR FAMILIAL ALZHEIMER-DISEASE - A POSSIBLE CLUE TO THE HIGHER INCIDENCE OF ALZHEIMER-DISEASE IN WOMEN

Late-onset Alzheimer disease (AD) is associated with the Apolipoprotei n E (APOE)-epsilon 4 allele. In late-onset familial AD, women have a s ignificantly higher risk of developing the disease than do men. The ai m of this study was to determine whether the gender difference in fami lial AD is a function of APOE genotype. We studied 58 late-onset famil ial AD kindreds. Kaplan-Meier survival analysis was used to assess gen otype-specific distributions of age at onset. Odds ratios were estimat ed by logistic regression with adjustment for age and by conditional l ogistic regression with stratification on families. All methods detect ed a significant gender difference for the epsilon 4 heterozygous geno type. Zn women, epsilon 4 heterozygotes had higher risk than those wit hout epsilon 4; there was no significant difference between epsilon 4 heterozygotes and epsilon 4 homozygotes. In men, epsilon 4 heterozygot es had lower risk than epsilon 4 homozygotes; there was no significant difference between epsilon 4 heterozygotes and those without epsilon 4. A direct comparison of epsilon 4 heterozygous men and women reveale d a significant twofold increased risk in women. We confirmed these re sults in 15 autopsy-confirmed AD kindreds from the National Cell Repos itory at Indiana University Alzheimer Disease Center. These observatio ns are consistent with the increased incidence of familial AD in women and may be a critical clue to the role of gender in the pathogenesis of AD.