# How women’s reproductive life-history relates to cognitive decline and neuropathology in Alzheimer’s disease and related dementias

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $217,191

## Abstract

PROJECT SUMMARY
There is a critical need to understand conditions across the lifespan that may contribute to sex and gender
differences in Alzheimer’s disease and related dementias (ADRD) etiologies. We focus on reproductive history,
the most fundamental contributor to sex-specific health effects. Pregnancy and lactation are sensitive periods of
plasticity for human mothers as well as other mammals. During these life phases, permanent, re-organizing
effects transpire in various physiological systems, including the brain. Therefore, it is plausible that women’s
reproductive patterns modify the risks and mechanisms involved in neuropathogenesis across the lifespan. We
are galvanized by pilot results that both pregnancy and breastfeeding provided protection against women’s
ADRD onset as well as evidence of motherhood-related neurocognitive benefits in animal systems and human
postpartum neuroimaging studies. We capitalize on our trans-disciplinary perspective. Our project is cost-
efficient in utilizing available data and resources from an NIA-funded, large cohort study. We will analyze data
collected from 7,479 post-menopausal women age 65+ who participated in the Women’s Health Initiative (WHI)
Memory Study (WHIMS) and from the subset of 2,304 women in the WHI Study of Cognitive Aging (WHISCA).
We will also conduct new measurements of brain atrophy in existing MRI images that were collected from the
subset of 1,403 women in the WHIMS-MRI study. We will use a highly sensitive, voxel-wise approach that is
powerful for visualizing sub-regional patterns of disease-related atrophy. Aim 1 will examine how women’s history
of pregnancy relates to ADRD classification, verbal memory, hippocampal ischemic volume, and atrophy using
voxel-wise approaches to measure cortical gray matter thickness and subcortical gray matter density. Aim 2 will
examine how women’s history of breastfeeding relates to the same list of ADRD-related pathology outcomes.
Both aims will test the interaction of APOE-ε4 carrier status. The ε4 allele is associated with miscarriage, reduced
fertility, and weaker estrogenic neuroprotection compared to ε3 and ε2, in addition to its association with
enhanced AD risk in some demographic groups. We predict that pregnancy-related and breastfeeding-related
ADRD resilience will be weaker in ε4 carriers. Also, we suspect reproductive history could potentially exert
differential effects on etiological pathways involved in different forms of dementia. Therefore, we will conduct
exploratory analyses stratifying the cohort by global ischemia. After this project, we plan to pursue an R01 to
examine endocrine, immune, cardiovascular, and metabolic biomechanisms, working towards designing clinical
risk assessment tools. This project is responsive to the Notice of Special Interest: Sex and Gender Differences
in AD/ADRD which invites proposals on life course factors e.g., reproductive history, and sex-specific risk factors,
e.g., pregnancy. We address NIA’s...

## Key facts

- **NIH application ID:** 10740751
- **Project number:** 1R21AG079093-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Molly Maurer Fox
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $217,191
- **Award type:** 1
- **Project period:** 2023-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740751

## Citation

> US National Institutes of Health, RePORTER application 10740751, How women’s reproductive life-history relates to cognitive decline and neuropathology in Alzheimer’s disease and related dementias (1R21AG079093-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10740751. Licensed CC0.

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