# 17 alpha-estradiol as a potential protective therapeutic against development of Alzheimer's disease

> **NIH NIH F31** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $37,214

## Abstract

PROJECT SUMMARY
 The two largest primary risk factors for late onset Alzheimer’s Disease (AD) in humans are aging and the
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 the lifespan and health parameters of male mice. While
lifespan was not improved in females, limited studies have sought to uncover what other potential benefits
females may experience with 17αE2. 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 age-related phenotypes, 17αE2 may
preferentially improve outcomes in the context of APOE4 genotype. In this proposal, I will test the hypothesis
that 17αE2 protects against aging phenotypes caused by the APOE4 allele that promote AD
development. To test this hypothesis, I will use two different mouse models of AD risk and early pathogenesis:
knock-in of human APOE3 or APOE4, and knock-in of human APOE3 or APOE4 with 5xFAD transgenes
(EFADs). Aim 1 determines the systemic and neural effects of 17αE2 on APOE3 and APOE4 early middle-aged
female and male mice, while Aim 2 focuses on the role of 17αE2 in the development of AD pathology, including
amyloid beta plaques and gliosis, using E3FAD and E4FAD mice. Our preliminary data indicate genotype
differences in the impact of 17αE2 across multiple outcomes. We maintained 10-month-old APOE3 or APOE4
targeted replacement male mice on normal chow in the absence or presence of 14.4 ppm 17αE2 for 20 weeks.
APOE4 mice exhibited an aged phenotype compared to APOE3, with higher frailty and impairments in multiple
metabolic measures. Treatment with 17αE2 yielded improvements in both APOE genotypes but with greater
effects in APOE4 mice on several measures including body weight, plasma leptin, and hepatic steatosis. 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 measures
across genotypes, it shows the strongest effects in the APOE4 genotype. Completion of the proposed studies
will further emphasize the need to consider both genotype and sex when assessing longevity-promoting
compounds as AD therapeutics. The well-known importance of age in AD, along with the progeroid effect of
APOE4, highlight the potential to use geroscience and longevity-promoting drugs to intervene in AD
development.

## Key facts

- **NIH application ID:** 10930827
- **Project number:** 5F31AG084279-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Cassandra Joan McGill
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $37,214
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930827

## Citation

> US National Institutes of Health, RePORTER application 10930827, 17 alpha-estradiol as a potential protective therapeutic against development of Alzheimer's disease (5F31AG084279-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10930827. Licensed CC0.

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