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

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The apolipoprotein E(APOE)ε4 allele is a confirmed genetic risk factor and theAPOEε2 allele is a protective factor related to late-onset Alzheimer's disease (AD). Intriguingly, recent studies demonstrated similar brain function alterations betweenAPOEε2 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 theAPOEε2 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 betweenAPOEε2 and ε4 alleles in the DMN may reflect the antagonistic pleiotropic properties and associate with their different AD risks.

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