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The apolipoprotein E  (APOE)  ϵ4 allele is a confirmed genetic risk factor and the  APOE  ϵ2 allele is a protective factor related to late-onset Alzheimer's disease (AD). Intriguingly, recent studies demonstrated similar brain function alterations between  APOE  ϵ2 and ϵ4 alleles, despite their opposite susceptibilities to AD. To address this apparent discrepancy, we recruited 129 cognitively normal elderly subjects, including 36 ϵ2 carriers, 44 ϵ3 homozygotes, and 49 ϵ4 carriers. All subjects underwent resting-state functional MRI scans. We hypothesized that aging could influence the  APOE  ϵ2 and ϵ4 allele effects that contribute to their appropriate AD risks differently. Using the stepwise regression analysis, we demonstrated that although both ϵ2 and ϵ4 carriers showed decreased functional connectivity (FC) compared with ϵ3 homozygotes, they have opposite aging trajectories in the default mode network—primarily in the bilateral anterior cingulate cortex. As age increased, ϵ2 carriers showed elevated FC, whereas ϵ4 carriers exhibited decreased FC. Behaviorally, the altered DMN FC positively correlated with information processing speed in both ϵ2 and ϵ4 carriers. It is suggested that the opposite aging trajectories between  APOE  ϵ2 and ϵ4 alleles in the DMN may reflect the antagonistic pleiotropic properties and associate with their different AD risks.

Opposite Neural Trajectories of Apolipoprotein E ϵ4 and ϵ2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease