# Estrogen therapy and APOE4 risk in Alzheimer's tested in female EFAD mice

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $635,706

## Abstract

The gene that controls expression of the apolipoprotein ε4 allele, APOE4, is the greatest genetic risk factor for
Alzheimer's disease (AD), increasing risk up to 15-fold compared to APOE3. Although this risk, associated with
enhanced amyloid-β (Aβ) accumulation, was discovered over 20 years ago, it has rarely been the focus of
therapeutic approaches; even less so, the critical link between female sex and the APOE4-induced risk for
dementia and AD. Female (♀) APOE4 carriers have a greater lifetime risk for developing AD, an increased rate
of cognitive decline and accelerated accumulation of Aβ compared to male (♂) APOE4 carriers, data consistent
with observations in ♀ and ♂ familial AD (FAD) transgenic mice. Estradiol (E2) would appear to be key to this
vulnerability: ablation of circulating E2 in pre-menopausal women by oophorectomy causes later cognitive deficits
that are reversed by estrogen therapy (ET). The effects of ET after natural menopause remain controversial,
particularly with regard to the “critical window” hypothesis stating that ET is beneficial only in the early
menopause window. A further concern is the unfavorable safety profile associated with ET resulting from the
Women's Health Initiative studies, requiring the development of safer ET alternatives (alt-ET). The goal of this
proposal is to determine the ability of ET and alt-ET to counteract the negative interaction of sex with APOE4 in
the novel preclinical EFAD mouse model (expressing human APOE +FAD mutations), establishing both the
preferred timing and APOE isoform selectivity of safe alt-ET for therapy or prophylaxis of AD. The EFAD mouse
was developed to study the interaction between human h-APOE and AD pathology by introducing the h-APOE
genotypes into 5xFAD mice: EFAD mice display advanced pathology in females vs. males and E4FAD vs.
E3FAD; and preliminary EFAD data suggests that ET after ovariectomy (OVX) protects against cognitive deficits.
Alt-ET to be studied are clinical selective estrogen receptor (ER) modulators (SERMs), raloxifene (Ral) and
bazedoxifene (Baz); the clinical Baz/E2 combination; and selective estrogen mimics (SEMs) with attenuated
gynecological effects. Aim 1: Establish the efficacy of ET (E2) treatment in OVX ♀EFAD mice with respect to
APOE genotype, measuring behavior/memory, apoE and Aβ biomarkers, and AD pathology. Aim 2: Establish
the “critical window” for ET in EFAD mice with respect to genotype. Aim 3: Test alt-ET in female EFAD mice as
transformational AD therapeutics. Dosing will be defined by measuring brain concentrations related to in vitro Kd
and EC50. To probe the roles of ER isoforms, mixed glial cultures from APOE-TR mice, will be studied using
selective pharmacological ER-probes. In vitro biomarkers (apoE, Aβ, ABCA1, cytokines) will mirror in vivo
biomarkers, allowing correlation with in vivo effects of ET and alt-ET, and development of an in vitro assay for
future discovery and optimization of Alt-ET for AD.

## Key facts

- **NIH application ID:** 9928380
- **Project number:** 5R01AG057008-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** MARY JO LADU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $635,706
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928380

## Citation

> US National Institutes of Health, RePORTER application 9928380, Estrogen therapy and APOE4 risk in Alzheimer's tested in female EFAD mice (5R01AG057008-04). Retrieved via AI Analytics 2026-06-04 from https://api.ai-analytics.org/grant/nih/9928380. Licensed CC0.

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