APOE is the most common genetic risk factor for late-onset Alzheimer’s disease (AD) and accelerated cognitive loss: AD risk is reduced by the APOE2 variant and increased by the APOE4 variant. Longevity follows the same pattern, increased by APOE2 and decreased by APOE4, which parallels advanced age as the single greatest risk factor for AD. Indeed, APOE genotype may regulate AD vulnerability in part by affecting aging processes. Consistent with this possibility, recent findings by our research team and others show that APOE4 modifies key outcomes linked with aging and AD risk, including elevated inflammation and metabolic outcomes. We propose studies of new longevity-promoting interventions with the synthetic steroid 17a-estradiol (17aE2) for potential attenuation of senescent changes in the brain and throughout the body that are associated with heightened AD risk. Pilot data with APOE4 mice predict that the benefits of the anti-aging intervention 17aE2 will be most robust for APOE4 and least for APOE2. The proposed studies will establish proof of principle for 17aE2 as an AD therapeutic, with efficacy predicted to be strongest in the APOE4 genotype. Because the majority of those with AD are APOE4 carriers, mitigating its impact would promote brain health throughout life.