# Modeling sex differences in Alzheimer's disease cognition and pathology

> **NIH NIH R56** · WEST VIRGINIA UNIVERSITY · 2020 · $581,298

## Abstract

Abstract Modeling sex differences in Alzheimer’s Disease cognition and pathology
There are significant differences between men and women in the incidence and prevalence of Alzheimer’s
Disease (AD). After menopause, women are more likely to develop AD, and symptoms of the disease including
cognitive impairment are more severe. These sex differences are further complicated by high cholesterol which,
at midlife, is a major risk factor for AD, and there is substantial interaction between estrogen and cholesterol.
There is a significant gap in our knowledge of how estrogen neuroprotection and cholesterol diet-associated
vulnerability converge because replacing estrogen or treating with cholesterol-lowering statins may not reverse
cognitive impairment and can even make it worse. We propose to model sex differences in AD and the
complicating effects of high cholesterol by studying cholesterol-fed male and female rabbits because they show
significant sex differences in AD-like pathology and cognition. Cholesterol-fed females develop beta amyloid
(Aβ) deposits more slowly than cholesterol-fed males and eliminating peripheral estrogen by ovariectomy more
than doubles Aβ levels, suggesting a protective role for estrogen against amyloid pathology. We have
preliminary data suggesting female cholesterol-fed rabbits remember trace eyeblink conditioning better than
cholesterol-fed males and that a cholesterol diet alters estrogen receptors alpha and beta which correlates with
a significant increase in serum and hippocampal levels of the cholesterol metabolite, 27-hydroxycholesterol (27-
OHC). 27-OHC is an endogenous estrogen receptor modulator that may play a role in learning and memory
because patients with mild cognitive impairment (MCI) and AD exhibit elevated 27-OHC levels and we have
preliminary data suggesting cholesterol-fed rabbits with elevated 27-OHC have memory deficits. We also have
new data showing sex differences in the transcriptional activity of estrogen receptors and expression of proteins
in the presynaptic active zone and postsynaptic density that are higher in female cholesterol-fed rabbits than
males. The present research focus on cholesterol-induced increases in 27-OHC has direct clinical relevance
because midlife hypercholesterolemia is a risk factor for AD and, importantly, 27-OHC is significantly elevated
in mild cognitive impairment and AD. In two specific aims, we will manipulate estrogen (Aim 1) and estrogen
receptors (Aim 2) in cholesterol-fed rabbits to test the hypothesis that sex differences in AD-like cognitive
impairment and pathology are a function of endogenous estrogen receptor modulation of downstream targets.
Using behavioral, electrophysiological, histochemical and molecular biological techniques, we will determine the
mechanisms by which endogenous estrogen receptor modulation by cholesterol diet-induced 27-OHC affects
memory, neural function, markers of cholesterol and Aβ processing, and Aβ and tau levels in male and fem...

## Key facts

- **NIH application ID:** 9914168
- **Project number:** 5R56AG057307-02
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** OTHMAN GHRIBI
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $581,298
- **Award type:** 5
- **Project period:** 2019-04-15 → 2021-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914168

## Citation

> US National Institutes of Health, RePORTER application 9914168, Modeling sex differences in Alzheimer's disease cognition and pathology (5R56AG057307-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9914168. Licensed CC0.

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