# Health of the cholinergic system and risk for Alzheimer's disease in post-menopausal women

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2022 · $212,661

## Abstract

Women are at increased risk for Alzheimer’s disease (AD). Notably at menopause, some women experience
a change in cognition. However, not all women experience negative effects of menopause on cognition. The
cognitive changes that occur at menopause have not yet been connected to late life risk for pathological aging
including AD. Thus, understanding the neurobiological factors related to individual differences in cognition at
menopause is critical for understanding normal cognitive aging and for determining risk for pathological aging.
The challenge in understanding the role of estrogen loss on the risk for AD is the long lag time between the
hormonal changes at menopause and the clinical manifestations of AD. Thus, identifying how the hormone
changes after menopause are related to AD risk will alter the risk calculus for postmenopausal women.
 The novel study proposed here will examine an established AD-related neurotransmitter-based mechanism
that may also underlie cognitive changes after menopause. We propose that the change in the hormonal milieu
at menopause interacts with the cholinergic system and other brain pathologies to influence a woman’s risk for
cognitive decline. Preclinical studies have shown that estrogen is necessary for normal cholinergic functioning
and its withdrawal leads to cholinergic dysfunction and cognitive impairment. It is important to determine whether
menopause-related cognitive changes correlate with both cholinergic functional integrity and established AD
biomarkers that portend increased risk for late-life cognitive impairment or dementia.
 This supplemental application will enhance the parent grant in two primary ways. First it will enable the
acquisition of medicinal mecamylamine (our anticholinergic challenge drug) that has become exceedingly difficult
to obtain in the last two years.
 Second, it will add a novel in-vivo cholinergic molecular imaging biomarker of the integrity/function of the
cholinergic neurotransmission system. This approach will use a novel positron emission tomography (PET)
radiotracer, [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV), that was developed for in-vivo assessment of brain
cholinergic function as it exhibits high binding affinity and specificity for the presynaptic vesicular acetylcholine
transporter (VAChT). [18F]FEOBV PET imaging will be used to greatly enhance our abilities to evaluate the
impact of early preclinical AD pathologies on the relationship between cholinergic integrity, early cognitive
alterations, and reproductive history.
 The public health significance of this study is that it will identify individual difference factors that are
associated with cognitive performance changes after menopause and their relationship to structural, functional,
and biomarker evidence of risk for later life cognitive dysfunction. Knowledge of these factors will serve to
advance personalized future risk-mitigation strategies for women including hormonal, medication, cognitive
remediation...

## Key facts

- **NIH application ID:** 10588361
- **Project number:** 3R01AG066159-04S1
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** JULIE A DUMAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $212,661
- **Award type:** 3
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10588361

## Citation

> US National Institutes of Health, RePORTER application 10588361, Health of the cholinergic system and risk for Alzheimer's disease in post-menopausal women (3R01AG066159-04S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10588361. Licensed CC0.

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