EVIDENCE FOR MAJOR GENE INHERITANCE OF ALZHEIMER-DISEASE IN FAMILIES OF PATIENTS WITH AND WITHOUT APOLIPOPROTEIN-E EPSILON-4

Apolipoprotein E (APOE) genotype is the single most important determin ant to the common form of Alzheimer disease (AD) yet identified, Sever al studies show that family history of AD is not entirely accounted fo r by APOE genotype, Also, there is evidence for an interaction between APOE genotype and gender, We carried out a complex segregation analys is in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer G enetic Epidemiology study in order to derive models of disease transmi ssion which account for the influences of APOE genotype of the proband and gender, In the total group of families, models postulating sporad ic occurrence, no major gene effect, random environmental transmission , and Mendelian inheritance were rejected, Transmission of AD in famil ies of probands with at least one epsilon 4 allele best fit a dominant model, Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking epsilon 4, but a more co mplex genetic model or multiple genetic models may ultimately account for risk in this group of families, Our results also suggest that susc eptibility to AD differs between men and women regardless of the proba nd's APOE status, Assuming a dominant model, AD appears to be complete ly penetrant in women, whereas only 62%-65% of men with predisposing g enotypes develop AD. However, parameter estimates from the arbitrary m ajor gene model suggests that AD is expressed dominantly in women and additively in men, These observations, taken together with epidemiolog ic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility.