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

Background 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. Method To examine the effects at the earliest phases of AD development, we used 10‐month‐old APOE3 or APOE4 targeted replacement male mice maintained for 20 weeks on normal chow in the absence or presence of 14.4 ppm 17αE2. Mice were evaluated on various metabolic, behavioral, and molecular measures. Result Our initial results indicate genotype differences in the impact of 17αE2 across multiple outcomes. APOE4 mice were impaired across metabolic measures including body weight, plasma leptin, and hepatic steatosis, and 17αE2 treatment significantly attenuated these metabolic phenotypes. APOE4 mice exhibited an aged phenotype compared to APOE3 , notably with higher frailty indices; however, 17αE2 treatment reduced the frailty index more strongly in APOE4 mice compared to APOE3 . Interestingly, transcriptomic analysis of isolated microglia from both APOE3 and APOE4 17αE2 treated mice displays a downregulation of genes relating to inflammation and upregulation of those in metabolic pathways. Conclusion These data confirm and extend prior findings that APOE4 is linked to progeroid effects both peripherally and neurally, outcomes associated with AD risk. Importantly, although 17αE2 significantly improved a range of measure across genotypes, it showed the strongest effects in the APOE4 genotype. This research was funded by the Cure Alzheimer’s Fund.