Gene-environment interactions: lifetime cognitive activity, APOE genotype, and β-amyloid burden

Abstract

Carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of β-amyloid (Aβ) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Aβ pathology, which could be particularly beneficial in APOE ε4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE ε4 allele in relation to brain Aβ burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 ± 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE ε4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Aβ deposition, quantified using [11C] Pittsburgh-compound-B (PIB)-PET. As expected, the ε4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in ε4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Aβ.

Keywords: APOE; Alzheimer's disease; PIB-PET; aging; lifestyle activity; β-amyloid.

Figure 1.

Visualization of the significant interaction between APOE ε4 carrier status (ApoE4+, ApoE4−) and lifetime cognitive activity. A, B, Figures demonstrate that cortical PIB retention is reduced in ε4 carriers with greater lifetime cognitive activity. A, The graph conceptualizes APOE ε4 carrier status as moderator variable and shows predicted cortical PIB retention (solid circles) in ε4 carriers (red) and noncarriers (black) for low- and high-lifetime cognitive activity; lines demonstrate linear trends. In addition, observed cortical PIB retention is depicted for heterozygous ε4 carriers (red circles), homozygous ε4 carriers (red triangles) and noncarriers (gray circles). Variables are residuals after adjusting for age, gender, and years of education. B, Predicted voxelwise cortical PIB retention in ε4 carriers and noncarriers for low- and high-lifetime cognitive activity (adjusted).