Longevity-promoting interventions represent a promising strategy to mitigate brain aging and reduce Alzheimer's disease (AD) risk. The NIA Interventions Testing Program identified the weak estrogen 17α-estradiol (17αE2) as a compound that extends healthspan and lifespan in mice, with effects observed primarily in males. Our recent work demonstrated that 17αE2 healthspan benefits were modulated by human apolipoprotein E ( APOE ) genotype such that aging phenotypes were improved more strongly in middle-aged male mice with targeted-replacement of the AD-associated APOE4 allele compared to APOE3 , the risk neutral and most common APOE allele. Here, we tested whether APOE -dependent, AD-relevant benefits of 17αE2 observed in males extend to females. Specifically, we treated 12-month-old APOE3 and APOE4 targeted-replacement female mice for 6 months with chow containing 0 or 14.4ppm 17αE2. We find that relative to APOE3 , APOE4 genotype largely exhibits more robust systemic phenotypes associated with aging, including increased adiposity, impaired glucose tolerance, and reduced energy expenditure. Further, we observe that treatment with 17αE2 yields modest improvements in some outcomes, including decreased adiposity and increased lean mass, glucose tolerance, and energy expenditure, though significant benefits are found only in APOE4 females. In the CNS, we observed mixed effects of APOE genotype on behavioral performance and indices of brain aging, with APOE4 females performing worse in the Barnes Maze and having higher levels of the AD-related peptide soluble β-amyloid, but no APOE genotype differences in cortical lipid raft oxidative damage. In contrast to its systemic effects, 17αE2 did not significantly improve neural outcomes in APOE3 or APOE4 females. These findings address the impact of biological sex on established protective effects of a longevity-promoting intervention against APOE4 phenotypes, which have significant relevance to the prevention of age-related conditions including metabolic dysfunction, cognitive impairment and vulnerability to AD.
