MULTIPLE ETIOLOGIES FOR ALZHEIMER-DISEASE ARE REVEALED BY SEGREGATIONANALYSIS

We have evaluated several transmission models for Alzheimer disease (A D), using the logistic regressive approach in 401 nuclear families of consecutively ascertained and rigorously diagnosed probands. Models po stulating no major gene effect, random environmental transmission, rec essive inheritance, and sporadic occurrence were rejected under varied assumptions regarding the associations among sex, age, and major gene susceptibility. Transmission of the disorder was not fully explained by a single Mendelian model for all families. Stratification of famili es as early- and late-onset by using the median of family mean onset a ges showed that, regardless of the model studied, two groups of famili es fit better than a single group. AD in early-onset families is trans mitted as an autosomal dominant trait with full penetrance in both sex es and has a gene frequency of 1.5%. Dominant inheritance also gave th e best fit of the data in late-onset families, but this hypothesis was rejected, suggesting the presence of heterogeneity within this subset . Our study also revealed that genetically nonsusceptible males and fe males develop AD, indicating the presence of phenocopies within early- onset and late-onset groups. Moreover, our results suggest that the hi gher risk to females is not solely due to their increased longevity.