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

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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 may catalyze AD pathology in women at risk for AD, and is significant in providing strong scientific justification for further study of inflammation and neural activity and FC as AD mechanisms. Results of our study will inform development of interventions targeting stress and inflammation to reduce AD risk.