Opposite Neural Trajectories of Apolipoprotein E {epsilon}4 and {epsilon}2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease

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

Source: Cerebral Cortex - March 10, 2016 Category: Neurology Authors: Shu, H., Shi, Y., Chen, G., Wang, Z., Liu, D., Yue, C., Ward, B. D., Li, W., Xu, Z., Chen, G., Guo, Q., Xu, J., Li, S.-J., Zhang, Z. Tags: Original Articles Source Type: research