The presence of an e4 allele of the apolipoprotein E gene (APOE ε4) is considered the strongest genetic risk factor for Alzheimer’s disease (AD) in the US. Evidence suggests that APOE ε4 carriers have worse memory performances compared to APOE ε4 non-carriers in cognitively normal older adults and that female APOE ε4 carriers are at greater risk of AD compared to male carriers. Recent advancements in estimating biological age using DNA methylation markers may enhance understanding of the associations between sex and APOE ε4 on cognitive aging. Thus, the current study aimed to investigate whether associations between APOE ε4 status and memory vary according to rates of biological aging, using a DNA methylation age biomarker, in older men and women without dementia.

Cross-sectional data were obtained from 1771 older adults enrolled in the 2016 wave of the Health and Retirement Study (Mean age = 75, SD = 7; 57% female; 76% non-Hispanic white). The standardized residual from regressing chronological age on the epigenetic clock “DNAGrimAge” was used as a measure of the aging rate. A series of ANCOVAs with Bonferroni corrected post hoc pairwise tests, adjusting for education, white blood cell count, chronological age, and depressive symptoms were used to test the main and interaction effects of APOE ε4 status (non-carriers = 0; carriers = 1) and aging rates, defined as 1 standard deviation below (i.e., slow rate), or above (i.e., fast rate) sex-specific mean rate (i.e., average) of aging, on a standardized composite measure of verbal memory. Alpha was set at .05 and all raw scores were converted to z-score metric prior to analyses.

APOE ε4 female carriers with slow rates of aging (n = 34) had significantly better memory performances compared to APOE ε4 female carriers with fast rates of aging (n = 41), mean difference = .61, p = .006, and average rates of aging (n = 170), mean difference = .44, p = .017. There was no effect of aging rate on memory in the female non-carriers and there were no significant differences in memory performances based on rates of aging in either male APOE ε4 carriers or non-carriers.

Although the presence of the APOE ε4 has previously been shown to represent a stronger risk of AD for women compared to men, results from the current study suggest that slower rates of aging in this high-risk group may confer protection against clinical symptoms (i.e., memory impairment). Conversely, faster than average aging in female APOE ε4 carriers may represent a group at greater risk of memory impairment due to AD. However, longitudinal studies with larger sample sizes are needed to evaluate the risk of dementia/memory impairment based on rates of aging in female APOE ε4 carriers.