Protection Against Alzheimer’s Disease with Longevity-Promoting Intervention 17a-Estradiol

Aging is the single greatest risk factor for the development of Alzheimer’s disease (AD). Thus, one compelling approach to prevent and perhaps treat AD is to utilize interventions known to inhibit pathways that drive aging. Towards this end, recent advances in the field of geroscience have rigorously identified several factors that delay aging and consequently improve healthspan and longevity in rodent models. Arguably, the most promising of these candidate therapeutics is 17a-estradiol (17aE2), a compound related to estrogen that has been shown in mice to not only increase lifespan but also protect the brain and peripheral organs against markers of aging. In our prior Cure Alzheimer’s Fund (CAF) award, we studied the effects of 17aE2 in mice genetically engineered to contain human forms of the apolipoprotein E (APOE) gene. The APOE4 variant of APOE is the most significant genetic risk factor for AD and is associated with accelerated aspects of aging and reduced lifespan in humans and rodents. We observed that 17aE2 protected against aging in APOE mice with particular efficacy in mice carrying the AD-associated APOE4. Importantly, 17aE2 improved learning and memory and reduced levels of AD markers in the brain (oxidative damage, accumulation of the protein b-amyloid). Collectively, findings in the field paired with our recent CAF-supported advances suggest that 17aE2 has strong potential as a therapeutic intervention for preventing AD, perhaps especially in carriers of APOE4. This proposal will test the hypothesized efficacy of 17aE2 in an established mouse model of AD, an essential step in developing drugs for clinical use. In addition, we will compare the effects of 17aE2 in AD mice with human APOE3 (the most common form) versus APOE4 and in males versus females. Completing the proposed preclinical studies will establish proof-of-principle that 17αE2 can be used as a geroprotective AD therapeutic and provide a platform for further clinical development of 17aE2 as a novel potential drug against brain aging and AD.