# Perimenopause in APOE4 Brain: Obesity and Alzheimer's Pathobiology

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2020 · $271,496

## Abstract

PROJECT SUMMARY – PROJECT 2
The goal of our Program Project is to discover the biological transformations that occur in the brain during the
perimenopausal transition that can result in phenotypes predictive of risk for development of AD pathology. Our
focus is on the primary genetic risk factor for late-onset AD, the ε4 allele of apolipoprotein E (ApoE4), and how
it is disproportionally affects AD risk in women. In particular, we will investigate interactions between several
significant risk factors for AD: age, the ApoE4, and female sex. In Project 2, our specific emphasis is how
ApoE4 interacts with female sex, perimenopause and adiposity to cooperatively drive development of AD
pathology. Perimenopause initiates the age-related depletion of ovarian hormones in women. Perimenopause
is also linked with increases in body weight and adiposity that often lead to obesity, an established risk factor
for the development of AD. Significantly, adiposity and obesity are not only regulated by ovarian hormones, but
also are known to impair bioenergetics and increase inflammation. Thus, perimenopause creates a dangerous
convergence of AD risk factors in middle-aged women that we hypothesize is exacerbated by ApoE4. We
hypothesize that the central unifying link between AD, ApoE, obesity and estrogen is inflammation. Pro-
inflammatory pathways can function as critical driving forces in AD pathogenesis, are elevated by both ApoE4
genotype and obesity, and are inhibited by estrogen. To investigate these relationships, we propose three
specific aims that are highly collaborative across all Cores and Projects. Specific Aim 1: ApoE genotype
interactions in the regulation of inflammation and Alzheimer's pathways. We will compare the effects of ApoE
alleles on expression of AD- and inflammation-related genes, AD neuropathology, metabolism, and cognition
Specific Aim 2: Obesity and ApoE genotype interactions with female sex in the regulation of inflammation and
Alzheimer's pathways. We will determine how ApoE status interacts with obesity in the regulation of AD- and
inflammation-related pathways, AD neuropathology, metabolism and cognition. Specific Aim 3: Hormone
interventions for protection against inflammation and Alzheimer's pathways associated with ApoE genotype,
obesity and perimenopause. We will evaluate the efficacy of estrogen-based hormone therapies in attenuating
the effects of ApoE4, in the presence and absence of obesity, during both perimenopause and late
menopause.

## Key facts

- **NIH application ID:** 9961470
- **Project number:** 5P01AG026572-15
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** CHRISTIAN J PIKE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $271,496
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961470

## Citation

> US National Institutes of Health, RePORTER application 9961470, Perimenopause in APOE4 Brain: Obesity and Alzheimer's Pathobiology (5P01AG026572-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9961470. Licensed CC0.

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