Although it is clear that apoE plays an important role in the genetics of late-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 available on the number and contribution of additional genes. We estimated the number of additional quantitative-trait loci and their contribution to the 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 additional loci make a contribution to the variance in age at onset of late- onset 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 apoE. Additionally, we confirmed previous findings of a dose effect for the apoE ε4 allele, a protective effect for the ε2 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 make a difference of ≤17 years in age at onset of AD, our estimate of the contribution of apoE (7%-9%) to total variation in onset of AD is somewhat smaller than that which has previously been reported. Our results suggest that several genes that have not yet been localized may play a larger role than does apoE in late-onset AD.