# Examining the impact of sex and hormones on the progression of autosomal dominant Alzheimer's disease

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $135,070

## Abstract

Summary
Females may be more susceptible to Alzheimer’s disease (AD)-pathology, yet, in the early stages of AD, females
perform better on verbal memory tests than males with similar levels of pathology. Nonetheless, despite this
early verbal memory advantage, as disease progresses, females show faster cognitive decline. Thus, more
research is needed to better characterize sex differences in AD biomarker progression, and to clarify potential
mechanisms of cognitive resiliency or vulnerability to AD-pathology across the disease spectrum. To address
these critical knowledge gaps, I will capitalize on our ongoing longitudinal biomarker study with the largest
autosomal dominant AD kindred due to a single mutation (E280A) in the Presenilin-1 gene (PSEN1). PSEN1
mutation carriers are genetically determined to develop early-onset dementia, with mild cognitive impairment
emerging at a median age of 44 and dementia at age 49. This extraordinary cohort offers the opportunity to
examine sex differences in AD with few age-related confounds and methodological challenges. To this end, the
candidate proposes: (1) training objectives to establish expertise in sex biology, longitudinal and multivariate
modeling, and multimodal neuroimaging data, which together will further career development into an
independent clinical researcher in AD; (2) a research objective to examine sex differences in the accumulation
of AD-related pathology, neurodegeneration, and cognitive decline, and the potential role of steroid hormones in
autosomal dominant AD; (3) a team of mentors and advisors to ensure the candidate’s success, with expertise
in autosomal dominant AD (Dr. Yakeel Quiroz), biological sex differences (Dr. Jill Goldstein), sporadic AD (Dr.
Reisa Sperling), multimodal neuroimaging (Dr. Chen), sex-specific differences and risk in AD (Dr. Michelle
Mielke), and longitudinal and multivariate modeling (Dr. Hui Zheng). The proposed specific aims are to
determine the: (1) effect of sex on AD-related pathology and neurodegeneration in PSEN1 mutation carriers; (2)
effect of sex and AD biomarkers on cognitive decline in PSEN1 mutation carriers; (3) effect of steroid hormones
on AD biomarker accumulation and cognitive decline in PSEN1 mutation carriers. This proposed research is
innovative for investigating longitudinal sex differences in autosomal dominant AD using multimodal
neuroimaging and examining the role of steroid hormones in AD biomarker abnormalities and cognitive decline.
The proposed research is significant because further understanding of sex differences is crucial to inform
research on prevention, early detection, design of clinical trials, and development of treatments. Overall, this
project and training plan will promote the candidate’s career development by facilitating an independent
program of research examining sex differences in AD and elucidating mechanisms of AD risk and resilience to
inform precision interventions and treatments.

## Key facts

- **NIH application ID:** 10449410
- **Project number:** 1K99AG073452-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Clara Vila Castelar
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $135,070
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449410

## Citation

> US National Institutes of Health, RePORTER application 10449410, Examining the impact of sex and hormones on the progression of autosomal dominant Alzheimer's disease (1K99AG073452-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10449410. Licensed CC0.

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