Opposite Neural Trajectories of Apolipoprotein E Iμ4 and Iμ2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease

The apolipoprotein E (APOE) I mu 4 allele is a confirmed genetic risk factor and the APOE I mu 2 allele is a protective factor related to late-onset Alzheimer's disease (AD). Intriguingly, recent studies demonstrated similar brain function alterations between APOE I mu 2 and I mu 4 alleles, despite their opposite susceptibilities to AD. To address this apparent discrepancy, we recruited 129 cognitively normal elderly subjects, including 36 I mu 2 carriers, 44 I mu 3 homozygotes, and 49 I mu 4 carriers. All subjects underwent resting-state functional MRI scans. We hypothesized that aging could influence the APOE I mu 2 and I mu 4 allele effects that contribute to their appropriate AD risks differently. Using the stepwise regression analysis, we demonstrated that although both I mu 2 and I mu 4 carriers showed decreased functional connectivity (FC) compared with I mu 3 homozygotes, they have opposite aging trajectories in the default mode network-primarily in the bilateral anterior cingulate cortex. As age increased, I mu 2 carriers showed elevated FC, whereas I mu 4 carriers exhibited decreased FC. Behaviorally, the altered DMN FC positively correlated with information processing speed in both I mu 2 and I mu 4 carriers. It is suggested that the opposite aging trajectories between APOE I mu 2 and I mu 4 alleles in the DMN may reflect the antagonistic pleiotropic properties and associate with their different AD risks.