Heritability of plasma amyloid β in typical late-onset Alzheimer's disease pedigrees

Plasma amyloid β42 peptide (Aβ42) levels are significantly elevated in all genetic forms of early-onset Alzheimer's disease caused by familial Alzheimer's disease mutations or Down's syndrome. Moreover, recent studies have determined that both plasma Aβ42 and Aβ40 levels are significantly elevated in late-onset Alzheimer's disease (LOAD) patients, their cognitively normal first-degree relatives, and members of typical LOAD families when compared to appropriate controls. To determine the magnitude of the genetic component affecting plasma Aβ levels, we estimated the heritability of plasma Aβ42 and Aβ40 in 15 extended, multigenerational LOAD pedigrees, using a variance components method. Heritability estimates as high as 73 and 54% were found for plasma Aβ42 and Aβ40 levels, respectively. Inclusion of the ApoE ε4 dosage as a covariate was not found to have a significant effect on the heritability of these traits. These results suggest that genetic determinants other than ApoE account for a very substantial percentage of the phenotypic variance in plasma Aβ levels. The high heritability and the significant elevation of these traits in LOAD pedigrees suggest that at least some of the genetic determinants of plasma Aβ levels may lead to elevated Aβ and LOAD in these families. Thus, we suggest that plasma Aβ levels are quantitative traits that may be excellent surrogate markers for use in linkage analysis to identify loci that are important in typical LOAD.