The apolipoprotein ε4 (APOE ε4) allele is most commonly associated with increased risk for late-onset Alzheimer's disease (AD). However, recent longitudinal studies suggest that these risks are overestimated; most ε4 carriers will not develop dementia in their lifetime. In this article, we review new evidence regarding the impact of APOE ε4 on cognition among healthy older adults. We discuss emerging work from animal models suggesting that ε4 impacts brain structure and function in multiple ways that may lead to age-related cognitive impairment, independent from AD pathology. We discuss the importance of taking an individualized approach in future studies by incorporating biomarkers and neuroimaging methods that may better disentangle the phenotypic influences of APOE ε4 on the aging brain from prodromal AD pathology.
Keywords: Alzheimer’s risk; blood–brain barrier; cognitive aging; inflammation; neuronal dysfunction.
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