# Perimenopause in APOE4 Brain: Clinical Outcomes and Global Impact

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2020 · $454,011

## Abstract

PROJECT SUMMARY – PROJECT 3 
The three major risk factors for Alzheimer's disease are age, female gender and ApoE4 genotype. AD can be 
divided into two groups by age at onset: early onset (onset < 65 years; EOAD) and late onset (onset > 65 
years; LOAD). Human ApoE has three major isoforms: E2, E3, and E4. APOE4 is the strongest and most 
highly replicated genetic risk factor for late-onset AD (LOAD). One and two copies of APOE4 increase by a 
3.7- and 12-fold AD risk and decrease the age of onset by 8 to 15 years relative to APOE3/3 carriers. Findings 
from the first four years of our program project indicate that the perimenopause transition leads to a 
bioenergetic crisis in rat brain which activates a cascade of adaptive responses associated with an 
Alzheimer's-like phenotype. To advance both mechanistic understanding and clinical translation, we focus the 
renewal of our program project on the hypothesis that ApoE4 positive females experience a triple hit: 1) ApoE4 
genotype; 2) Aging and 3) Perimenopause. We propose that it is the perimenopausal bioenergetic shift in 
brain that creates greater risk of AD in women with a single copy of the APOE4 gene. The objective of this 
study is to 1) determine whether the perimenopausal transition in women is a transition state of risk for 
prodromal AD and 2) whether the ApoE4 genotype is a modifier that accelerates clinical indicators of risk of 
Alzheimer's disease that emerge during the perimenopause. Outcomes of these analyses will provide evidence 
regarding early stage development of three indicators of Alzheimer's risk, hypometabolism, brain atrophy and 
beta amyloid deposition. We have developed 3 approaches to test this hypothesis: a) a prospective molecular 
and neuroimaging study of 150 women; b) determination of the effect of the APOE4 genotype in 600 
postmenopausal women on cognitive decline from the USC Atherosclerosis Research Unit, the Elite Trial; c) 
determination of the effect of the APOE4 genotype and menopause on the lifespan trajectories of 
approximately 5,000 women derived from 10,000 MRI derived brain volume metrics and clinical data available 
through the ENIGMA working groups. We will also analyze 33,195 subjects (men and women from ENIGMA) 
with MRIs and genomes for the effect of sex (males vs females), ApoE4 genotype using a meta-regression 
model. We hypothesize that females and ApoE (e2/e3/e4 allele) risk loading will also demonstrate accelerated 
hypometabolic phenotype and an earlier decrease in hippocampal volumes. This project is truly a multi- 
disciplinary effort bringing together a strong investigative team. Drs. Roberta Brinton (USC Schools of 
Pharmacy and Medicine), Meng Law (USC School of Medicine-Neuroradiology), Paul Thompson and Arthur 
Toga (USC School of Medicine-Institute of Neuroimaging and Informatics with the Laboratory of Neuro Imaging 
(LONI), Howard Hodis (USC School of Medicine), Wendy Mack (USC School of Medicine). Our collaborator Dr. 
Lisa M...

## Key facts

- **NIH application ID:** 9961471
- **Project number:** 5P01AG026572-15
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Meng Law
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,011
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961471

## Citation

> US National Institutes of Health, RePORTER application 9961471, Perimenopause in APOE4 Brain: Clinical Outcomes and Global Impact (5P01AG026572-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961471. Licensed CC0.

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