# Influence of the Menopausal Transition and Lifetime Ovarian Exposure on Neural Metabolism, Connectivity and Pathology

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $830,324

## Abstract

Women are significantly more likely to develop Alzheimer’s disease than men, making up 2/3 of all AD cases.
Growing evidence suggests that this difference is related to the decline in ovarian hormone levels experienced
by women at midlife through menopause. Women who experience menopause later in life, and thus have a
longer lifespan exposure to ovarian hormones, are less likely to develop AD, suggesting that ovarian hormones
provide some protection against the development of AD pathology.
 Reduced brain metabolism and disruption of intrinsic network connectivity are two early indicators of
the development of AD pathology observable at midlife. As ovarian hormones, particularly estrogen, are
potent regulators of both glucose metabolism and synaptic plasticity, they might provide protection against
hypometabolism and network disruption, which would be removed by menopause. Recent studies provide
support for this view, indicating that postmenopausal women show reduced neural metabolic activity compared
to premenopausal women. Notably, the brain regions showing hypometabolism following menopause,
including multiple central nodes of the default mode network, match the pattern of hypometabolism and
amyloid deposition seen in AD. Similarly, studies from our laboratory and others have indicated that changing
ovarian hormone levels can influence the connectivity of the brain’s intrinsic networks, notably the default
mode network, whose connectivity is compromised in AD and has been previously shown to predict memory
function. However, studies relating menopause to these mechanisms of AD pathology are few, and many rely
on small sample sizes. Additionally, few studies have simultaneously examined the effects of menopause on
metabolism and connectivity, so the combined influence of these factors on AD risk is not well understood.
 While these findings point to a possible mechanism for increased AD risk following menopause, they do
not explain the protective effect observed from prolonged developmental ovarian exposure. Here we propose
that reductions in ovarian hormones over the menopausal transition lead to hypometabolism, promoting AD
pathology and disrupted network connectivity, but greater lifetime exposure to ovarian hormones moderates
these effects. To test this hypothesis, we will longitudinally follow perimenopausal women through the
menopausal transition over a 5 year period, using resting state fMRI and PET to measure changes in intrinsic
network connectivity, brain glucose metabolism, amyloid pathology, and cognitive function. Additionally, we
will collect these same measures in samples of premenopausal and postmenopausal women for comparison.
Each measure will be tested for their relationship to lifetime ovarian exposure to assess how developmental
ovarian hormone exposure influences menopause-related changes in each domain. The results of this
research provide a comprehensive model of the neural effects of menopause on AD and cognition, as wel...

## Key facts

- **NIH application ID:** 10807224
- **Project number:** 1R01AG085643-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JOSEPH M ANDREANO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $830,324
- **Award type:** 1
- **Project period:** 2024-03-15 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807224

## Citation

> US National Institutes of Health, RePORTER application 10807224, Influence of the Menopausal Transition and Lifetime Ovarian Exposure on Neural Metabolism, Connectivity and Pathology (1R01AG085643-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10807224. Licensed CC0.

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