Inter- and intra-chromosomal modulators of the APOE e2 and e4 effects on the Alzheimer's disease risk

The mechanisms of incomplete penetrance of risk-modifying impacts of apolipoprotein E (APOE) epsilon 2 and epsilon 4 alleles on Alzheimer's disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6,136 AD-affected and 10,555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE epsilon 2 allele (encoded by rs7412 polymorphism) and epsilon 4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the epsilon 2- and epsilon 4-associated AD risks, respectively, and identified epsilon 2-independent (rs2884183 polymorphism, 11q22.3) and epsilon 4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted epsilon 2- and/or epsilon 4-linked processes affecting the lipid and lipoprotein metabolism and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the epsilon 2- and epsilon 4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.