# Interactions of Sex and Gender Factors in Risk for Alzheimers Disease: Links Between Stress, Neural Activity, Inflammation, and Memory

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $483,790

## Abstract

PROJECT SUMMARY/ABSTRACT
Our proposed project focuses on understanding interactive effects of gender and sex on biological processes
implicated in Alzheimer’s disease (AD) risk. Gender is defined as an individual’s presentation as female or male,
and sex is defined by chromosomes and sex organs. Stress has both gender- and sex-linked components.
However, whether exposure to gender-linked stressors relates to neural and peripheral processes that promote
AD pathology, or whether sex hormones mediate these relationships, is unknown. In this proposal, we seek to
understand interactive effects of gender-linked stressor exposure and estrogen levels on memory, memory-
related neural activation, functional connectivity (FC) at rest, and peripheral inflammation. In doing so, the
proposal enables further study of AD mechanisms and development of interventions to reduce AD risk. The
objective of this proposal is to determine interactive effects of lifetime gender-linked stressor exposure and
estrogen levels on memory-related brain activation, resting state FC, peripheral inflammation, and verbal
memory in midlife women at risk for AD due to family history. The rationale for this project is that gender and
sex, indexed by stress exposures and estrogen, interactively promote changes in neural activation, FC, and
peripheral inflammation, which may facilitate AD pathology in women at risk for AD. Specific Aim 1 will investigate
interactive effects of gender-linked stressor exposure and estrogen levels on fMRI activation during memory
encoding, fMRI task performance, and default mode network (DMN) FC at rest. Specific Aim 2 will investigate
effects of gender-linked stressor exposure and estrogen interactivity on peripheral inflammation and verbal
memory. Specific Aim 3 will investigate the effects of peripheral inflammation on fMRI activation and FC at rest.
To achieve these aims, we will recruit participants from our Women’s Alzheimer’s Movement Prevention Center
at Cleveland Clinic, which serves women at risk for AD due to family history. Specific Aims 1-2 will include lifetime
gender-linked stressor exposure as a predictor, and as outcomes, a pattern separation fMRI task, a resting state
scan, plasma levels of pro-inflammatory cytokines, and neuropsychological measures of verbal memory. Specific
Aim 3 will use plasma levels of pro-inflammatory cytokines as predictors of task-based activation and resting
state FC. All analyses will include estradiol levels as a mediator. This study is expected to provide evidence
relating greater lifetime gender-linked stressor exposures to poorer verbal memory in women at risk for AD, as
well as to processes likely to contribute to sex and gender disparities in AD, such as hippocampal hyperactivation
and reduced DMN deactivation during memory encoding, greater posterior to anterior DMN FC at rest, and
higher peripheral inflammation. The proposed research is innovative in its focus on variables impacted by sex
and gender that ...

## Key facts

- **NIH application ID:** 10307848
- **Project number:** 1R01AG074392-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** JESSICA KIRKLAND CALDWELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $483,790
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307848

## Citation

> US National Institutes of Health, RePORTER application 10307848, Interactions of Sex and Gender Factors in Risk for Alzheimers Disease: Links Between Stress, Neural Activity, Inflammation, and Memory (1R01AG074392-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10307848. Licensed CC0.

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