The longevity‐promoting intervention 17α‐Estradiol protects against aging phenotypes in APOE4 mice

The two primary risk factors for late onset Alzheimer’s Disease (AD) are aging and APOE4 genotype. While the causal relationship between aging and AD is not well defined, shared phenotypes, such as decreased metabolic function and increased inflammation, are strong leads. APOE genotype may be linked to AD phenotype through the regulation of aging processes. The NIA Interventions Testing Program found that 17α‐estradiol (17αE2) treatment can increase male mouse lifespan. Since 17αE2 has been shown to act upon systemic and neural pathways that have also been associated with AD pathology, we propose that 17αE2 may constitute a pleiotropic intervention strategy. Further, because APOE4 is associated with impaired healthspan and lifespan, 17αE2 may preferentially improve outcomes in the context of APOE4 genotype.