Research on apolipoprotein E (APOE) has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD). However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.

The association between the apolipoprotein E epsilon4 allele and Alzheimer's disease (AD) is well-established. Functional neuroimaging research has supported a compensatory mechanism recruitment hypothesis whereby nondemented epsilon4 participants use additional cognitive resources to buffer against episodic memory declines in older age, a mechanism that is presumably associated with encroaching disease. However, recent studies have implicated a beneficial effect associated with the epsilon4 allele early in the life span. These studies suggest a revised hypothesis whereby epsilon4 persons perform better on cognitive measures early in the life span and then show greater recruitment of brain regions during performance to compensate for declines in older age caused by preclinical AD.

Previous studies of episodic memory report a greater extent of blood-oxygenation-level-dependent (BOLD) response in non-demented older adults with the apolipoprotein E epsilon-4 (APOE ε4) allele than in those without the allele. We conducted a functional MRI study to investigate whether APOE genotype is related to brain response to verbal paired-associate encoding and consolidation, particularly in the right hemisphere, among non-demented older adults. Structurally segmented volumes and BOLD response were measured in 13 non-ε4 and 12 ε4 subjects. The ε4 group displayed greater activation than the non-ε4 group in multiple right hemisphere regions for previously encoded word pairs relative to fixation. Activation within manually outlined hippocampal regions of interest also displayed genotype-specific dissociations consistent with whole brain analyses. Furthermore, this differential BOLD response occurred in the presence of equivalent behavioral and neuropsychological performances as well as comparable hippocampal and overall structural segmentation volumes between groups. Results implicate a widely distributed and interconnected network of right hemisphere brain regions that may be involved in compensating for APOE ε4-related deficiencies associated with verbal episodic memory encoding and consolidation.

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