17alpha‐estradiol improves systemic and neural outcomes in middle‐aged APOE4 mice

Abstract Background In this study, we investigate the hypothesis that recently identified longevity‐promoting intervention 17α‐estradiol (17αE2) will protect against senescent changes in brain and throughout the body that are associated with APOE4 and heightened AD risk. The most significant genetic factor for late‐onset Alzheimer’s disease (AD) is the apolipoprotein E gene ( APOE ): AD risk is reduced by the APOE2 variant and increased by the APOE4 variant. APOE genotype is associated with longevity in the same pattern, with APOE2 linked with increased and APOE4 with decreased lifespan. This is of particular interest as advanced age is the single greatest risk factor for AD. Indeed, APOE genotype may regulate AD vulnerability in part by affecting aging processes. Thus, compounds that increase health and longevity may be particularly relevant to APOE4 ‐associated AD risk. Method Male mice homozygous for human APOE3 or APOE4 were maintained on normal chow in the absence or presence of 14.4 ppm 17αE2 for 20 weeks, starting at age 10 months. Animals were assessed on a range of systemic metabolic, inflammatory, and frailty outcomes as well as on established areas of APOE4 ‐associated neural impairment, including neuroinflammation, neurogenesis, and cognition. Result In middle‐aged male mice, APOE4 genotype was associated with significantly poorer systemic and neural phenotypes relative to APOE3 genotype. In general, treatment with 17αE2 yielded improvements in both APOE3 and APOE4 mice across multiple measures, though the benefits were typically much stronger in APOE4 mice. For example, 17αE2 reduced body weight, plasma leptin, hepatic steatosis, and frailty index more strongly in APOE4 than APOE3 mice. Neural results are pending. Conclusion These data confirm and extend prior findings that APOE4 is associated with senescent effects both peripherally and neurally, outcomes linked with AD risk. Importantly, 17αE2 significantly improved a range of measures. This study will establish proof‐of‐principle for 17αE2 as an AD therapeutic with efficacy predicted to be strongest in APOE4 genotype. Given that the majority of AD cases in the U.S. are APOE4 carriers, mitigating the effects of APOE4 would have significant therapeutic potential. Supported by the NIA (RF1AG058068) and the Cure Alzheimer’s Fund.