# Understanding the relationship between female reproductive span and dementia risk

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $226,840

## Abstract

PROJECT SUMMARY
Despite robust evidence for a sex difference in Alzheimer’s disease and related dementias (ADRD), the
mechanisms behind this difference remain poorly understood. Given that reproductive hormones are a central
determinant of sex differences in brain structure and function, we hypothesize that factors that influence
lifetime reproductive hormone exposure (in particular estrogen exposure) are critical to understanding the
development of ADRD in women. The goal of the proposed study is to utilize existing data from the Swedish
Twin Registry – one of the largest population-based twin registries in the world – in order to understand the
genetic and environmental relationships underlying the association between female reproductive history and
ADRD. In Aim 1 we will use conventional and new data analytic methods to elucidate the degree to which the
association between female reproductive span and ADRD is due to shared genetic and environmental factors.
The genetic analysis of ADRD, and by extension any analysis which seeks to determine the degree of genetic
overlap with ADRD, is complicated by the fact that the relative risk of ADRD varies dramatically by age. We
will develop a genetically-informative survival analysis method to estimate the genetic and environmental
determinants of ADRD, as well as genetic and environmental correlations with reproductive span. In Aim 2, we
will test whether female reproductive span modifies the genetic and environmental determinants of ADRD.
Reproductive hormones like estrogen primarily exert their physiological influence by binding to hormone
receptors, which in turn modulate the expression of downstream genes. We hypothesize that due to this
mechanism, the heritability of ADRD will vary as a function of female reproductive span. In Aim 3, we will
determine how key women’s health factors – oral contraceptive use, parity, surgical menopause, and hormone
replacement therapy – impact the association between reproductive span and ADRD. We hypothesize that
these factors, which are crucial to understanding women’s health across the lifespan, will impact ADRD risk by
modifying the degree of lifetime estrogen exposure. This proposal will advance the field’s understanding of
how female reproductive history contributes to the etiology of ADRD by providing the first genetically-informed
analysis of the relationship between female reproductive span and ADRD conducted in twins, developing
analytic methods that are essential to genetically-informed analysis of ADRD, testing novel hypotheses
regarding whether lifetime estrogen exposure influences the genetic and environmental determinants of ADRD,
and finally determining how factors common to female reproductive history influence the relationship between
reproductive span and ADRD. The NIH has placed a major emphasis on the need for researchers to treat sex
as a biological variable, and to focus on those factors that contribute to sex differences in health and disease...

## Key facts

- **NIH application ID:** 10301699
- **Project number:** 1R21AG074212-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Matthew S Panizzon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $226,840
- **Award type:** 1
- **Project period:** 2021-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301699

## Citation

> US National Institutes of Health, RePORTER application 10301699, Understanding the relationship between female reproductive span and dementia risk (1R21AG074212-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10301699. Licensed CC0.

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