# Menopause, hormone therapy and Alzheimer's disease clinicopathology: An in vivo perspective

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $134,730

## Abstract

PROJECT SUMMARY / ABSTRACT
In the United States, approximately 6.2 million people live with a clinical diagnosis of Alzheimer disease
(AD). Postmenopausal women account for up to 70% of them. The overall goal of this proposed research is
to elucidate the progressive pathophysiological mechanisms by which menopausal hormone therapy (HT)
influences the risk of AD dementia in women. The applicant’s prior work showed that the timing of HT use
relative to menopause onset influences females’ susceptibility to the deposition AD pathology in later life. It
is critical that longitudinal cohort studies and randomized controlled trials are conducted to substantiate
these findings. During the K99 phase, the applicant will combine three observational studies (n=772) with
longitudinal biomarkers of AD, as measured with positron emission tomography (PET), to determine to
influence of HT and its timing on neocortical Aβ accumulation (over 6.5 years; Aim 1), region-specific tau
accumulation (over 4.2 years; Aim 1) and cognitive decline (over 7.4 years; Aim 2). To achieve these aims,
the applicant will leverage their existing strengths in neuroimaging, genetic-risk, cognitive neuroscience and
big data and gain expertise in following five areas of training: (1) PET-neuroimaging (2) Biofluids (3)
Statistics (4) Hormones and (5) Clinical trials (analytical approaches). With these skills, the applicant will be
well positioned in the R00 phase to conduct the final aim: to determine how early and late HT
randomization impacts the pathological progression of AD, relative to respective placebo groups, as
measured with multiple plasma AD biomarkers (Ab42/Ab40, p-tau181, p-tau217, p-tau231; Aim 3). In the R00,
the applicant will utilize existing samples from the Women Health Initiative; a landmark randomized
controlled trial on HT (n=3,472). Further, non-AD specific plasma biomarkers will be integrated to determine
how HT randomization impacts markers of astrogliosis (Glial fibrillary acidic protein; GFAP) and axonal
damage (Neurofilament light chain; NfL) and in addition, how GFAP and NfL may moderate the effect of HT
on the pathological progression of AD. A highly innovative component of this project is the use of cutting-
edge multi-modal measures of AD, wherein PET biomarkers and novel plasma biomarkers are integrated
across observations studies and a randomized controlled trial. Successful outcomes will alleviate
uncertainty regarding the downstream impact of HT on the brain and inform how exogenous hormones alter
the underlying neurobiology of AD. The project will highlight hormones as sex-specific risk factors
underlying sex differences in the prevalence of AD. These outcomes will have direct implications for AD
prevention and treatment strategies. For the applicant, this program will enhance a rapid transition to
independence using a short period of intensive training and mentorship from researchers at Massachusetts
General Hospital/Harvard Medical School, which wil...

## Key facts

- **NIH application ID:** 10885467
- **Project number:** 1K99AG083063-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Gillian Theresa Coughlan
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $134,730
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885467

## Citation

> US National Institutes of Health, RePORTER application 10885467, Menopause, hormone therapy and Alzheimer's disease clinicopathology: An in vivo perspective (1K99AG083063-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10885467. Licensed CC0.

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