APOE and Other Loci Affect Age-At-Onset in Alzheimer's Disease Families With PS2 Mutation

Abstract

Several kindreds of Volga German (VG) ancestry have a single PS2 mutation that causes an autosomal dominant form of Alzheimer's disease (AD). These families show a wide range in age-at-onset, which suggests the existence of modifying factors other than the PS2 mutation. To examine evidence for a genetic basis of variation in onset age, we performed a Bayesian oligogenic segregation and linkage analysis on nine VG families confirmed to have at least one affected PS2 carrier. This analysis simultaneously estimated the effects of APOE and PS2 and the number and effects of additional loci affecting AD age-at-onset. In addition, a family effect accounted for shared environmental effects. This analysis approach has the advantage of full use of the complete pedigree structure, as well as use of information on unsampled individuals with phenotypic data. These analyses provide evidence that APOE plays a small, but significant, role in modifying the ageat-onset in these VG families. The effects estimated for the APOE e3 and e4 genotypes were consistent with those estimated in previous analysis of late-onset AD families, with evidence for a dose-dependent relationship between number of e4 alleles and age-at-onset. We estimated an $83$70, $2,$6.5, and $8.5%, respectively. These results provide evidence that APOE and other loci modify onset in AD caused by PS2 mutation