The number of trait loci in late-onset Alzheimer disease

Although it is clear that apoE plays an important role in the genetics of l ate-onset Alzheimer disease (AD), evidence exists that additional genes may play a role in AD, and estimates of the total contribution of apoE to the variance in onset of AD vary widely. Unfortunately, little information is a vailable on the number and contribution of additional genes. We estimated t he number of additional quantitative-trait loci and their contribution to t he variance in age at onset of AD, as well as the contribution of apoE and sex, in an oligogenic segregation analysis of 75 families (742 individuals) ascertained for members with late-onset AD. We found evidence that four ad ditional loci make a contribution to the variance in age at onset of late-o nset AD that is similar to or greater in magnitude than that made by apoE, with one locus making a contribution several times greater than that of apo E. Additionally, we confirmed previous findings of a dose effect for the ap oE epsilon 4 allele, a protective effect for the epsilon 2 allele, evidence for allelic interactions at the apoE locus, and a small protective effect for males. Furthermore, although we estimate that the apoE genotype can mak e a difference of less than or equal to 17 years in age at onset of AD, our estimate of the contribution of apoE (7%-9%) to total variation in onset o f AD is somewhat smaller than that which has previously been reported. Our results suggest that several genes that have not yet been localized may pla y a larger role than does apoE in late-onset AD.