# Sex differences in the progression of Alzheimer's disease: is menopause the key?

> **NIH NIH R00** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $249,000

## Abstract

PROJECT SUMMARY
The overall goal of this proposed research is to elucidate the mechanisms that may confer increased
vulnerability to Alzheimer’s disease (AD)-related cognitive decline in females, using state-of-the-art multi-modal
neuroimaging, in both middle and older-aged adults. Females are often reported to exhibit greater rates of
clinical progression to AD dementia than males. The applicant’s preliminary data suggest, however, that
minimal sex differences exist in amyloid burden, implying other pathophysiologic mechanisms, such as tau,
may influence subsequent elevated risk of cognitive decline in older females. It is also critical to investigate the
early emergence of sex differences in AD biomarker accumulation during midlife, when sex and hormonal
factors may have a particular impact. During the K99 phase, the first aim will identify sex differences in AD
neuroimaging biomarkers of amyloid, tau and neurodegeneration in clinically-normal older adults. The second
aim will determine relationships between sex and baseline AD biomarkers on longitudinal rates of cognitive
decline in the same sample. The primary hypothesis, based on preliminary data, is that women will
demonstrate greater tau burden, neurodegeneration and rates of cognitive decline despite similar levels of
amyloid burden, likely due to an interaction between sex and APOE genotype. To accomplish these goals, the
applicant will leverage existing strengths in statistical modeling and cognitive neuroscience to gain expertise in
four critical areas of training: (1) multimodal imaging, (2) data harmonization, (3) longitudinal modeling, and (4)
sex biology. With the development of these skills, the applicant will be well positioned in the R00 phase to
conduct the final aim: to investigate sex differences in AD biomarker accumulation in middle-aged adults. In
addition, the candidate will focus on the influence of hormonal stage (pre-menopause, perimenopause, and
menopause) on rates of AD biomarker accumulation relative to age-matched males. A highly innovative
component of this project is the use of multimodal neuroimaging (positron emission tomography (PET) and
magnetic resonance imaging) and genetics to understand the mechanisms underpinning greater female risk for
AD. The proposed study will provide some of the first insights into sex-differences in regional tau-PET burden
in preclinical AD in middle and older-age adults. To boost statistical power for detecting sex effects in the K99
phase, data will be harmonized across three well-characterized, longitudinal cohorts of older adults (60-90
years). For the R00 phase, a similar approach will be employed to harmonize data across three longitudinal
cohorts of middle-aged adults (40-65 years). Elucidating sex-specific effects on Alzheimer’s disease (AD) risk
across the lifespan has far-reaching consequences for understanding the biological mechanisms that catalyze
AD risk, and also for better powering clinical trials to identify those ...

## Key facts

- **NIH application ID:** 10454290
- **Project number:** 5R00AG061238-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Rachel Frances Buckley
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454290

## Citation

> US National Institutes of Health, RePORTER application 10454290, Sex differences in the progression of Alzheimer's disease: is menopause the key? (5R00AG061238-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10454290. Licensed CC0.

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