Women have a greater lifetime risk of developing Alzheimer’s disease (AD) dementia than men, a sex/gender disparity that cannot be explained by female longevity alone. There is substantial evidence for sex differences in the effects of APOE £4 on risk for AD. While APOE e4 increases AD risk in both sexes, women who carry APOE e4 are disproportionately vulnerable to cognitive impairment and AD compared to their counterpart men. In contrast to APOE e4, APOE £2 is associated with slower cognitive decline and a lower risk of AD. Although a less robust literature, APOE e2 may also have sex-specific effects. Because APOE e2 is the rarest major APOE allele, well-powered studies are needed to examine sex-specific effects. The objective of the present study was to examine sex-specific associations of APOE e2 carriage with longitudinal cognitive decline in a large cohort of clinically unimpaired adults.

We used observational data from two sources: the National Alzheimer’s Coordinating Center (NACC) and the Rush Alzheimer’s Disease Center (ROS/MAP/MARS) studies. We included data from clinically unimpaired adults who were >50 years old at baseline who self-identified as non-Hispanic White (NHW) or non-Hispanic Black (NHB). Participants were categorized as APOE £2, £4, or £3/e3 carriers. APOE e2/e4 carriers were excluded. The same battery of neuropsychological tests was used to assess global cognition in participants from both data sources. Linear mixed models examined interactive associations of genotype (£2 or £4 vs. £3/£3), sex, and time on longitudinal cognition in NHW and NHB participants separately. Analyses were first performed in a pooled sample of NACC and ROS/MAP/MARS participants and if significant they were repeated separately in each data source.

Across both data sources, 9,766 NHW (mean (SD) age=73.0(9.00) years, mean (SD) education=16.3(2.83) years, n(%) women=6,344(65.0)) and 2,010 NHB participants (mean(SD) age=71.3(7.59) years, mean(SD) education=14.9(3.10) years, n(%) women=1,583(78.8)) met inclusion criteria. Sex modified the association between APOE £2 and cognitive decline in NHW (ß=0.097, 95% CI: 0.023-0.172, pint=.01) but not NHB participants (ß=-0.011, 95% CI: -0.153-0.131, pint=.9). In sex-stratified analyses of NHW participants, APOE £2 (vs. £3/£3) carriage was associated with attenuated cognitive decline in men (ß=0.096, 95% CI: 0.037-0.155, p=.001), but not women (ß=-0.001, 95% CI: -0.044-0.043, p=.97). In analyses comparing men and women APOE £2 carriers, men exhibited slower cognitive decline than women (ß=0.120, 95% CI: 0.051-0.190, p=.001). Analyses performed separately in NACC and ROS/MAP revealed the same pattern of male-specific APOE £2 protection in NHW participants in both data sources.

In light of the longstanding view that APOE £2 protects against AD and dementia, our results provide evidence that APOE £2 is associated with attenuated cognitive decline in men but not women among NHW adults. This male-specific protection may contribute to sex differences in AD-related cognitive decline. Our findings have important implications for understanding the biological drivers of sex differences in AD risk, which is crucial for developing sex-specific strategies to prevent and treat AD dementia.