Women Living with HIV: Cognitive Impact of Estrogen Receptors, Inflammation, and Aging

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Project Summary/Abstract Cognitive impairment is prevalent in older adults and females carry a disproportionately greater risk for cognitive deficits like dementia and Alzheimer's disease. While estrogen deficiencies have been linked to an increased risk of cognitive decline, the mechanism for this remains unclear. Evidence suggests that women living with HIV (WLH) are more likely to experience an earlier onset of menopause, thereby reducing the circulating estrogen levels. Additionally, within the population of people living with HIV (PLWH), women are at a higher risk for developing cognitive decline which tracks with data seen in the general population of people living without HIV. Thanks to the advancement of HIV treatments, PLWH are living longer, adding to the urgency to identify mechanisms underlying the acceleration of cognitive decline. The goal of this proposal is to determine the extent to which estrogen receptor expression and function predict cognitive decline in WLH. Leveraging the framework of the Atlanta Women's Interagency HIV Study (WIHS) cohort and the Emory SCORE U54, this project will test the hypothesis that HIV serostatus interacts with menopause to alter estrogen receptor subtype expression and that changes to estrogen receptor β are predictive of inflammatory and cognitive outcomes. Aim 1 will focus on the characterization of estrogen receptor subtype protein expression in PBMCs to establish a metric for understanding the expression of the two prominent estrogen receptor subtypes (α and β) and how they differ in the context of menopause and HIV. Aim 2 will establish inflammatory and cognitive profiles for the study participants using longitudinal timepoints to illuminate changes in both inflammatory and cognitive states that can be tracked over time. Data resulting from the evaluation of estrogen receptor subtype expression in the context of menopausal status and HIV status, coupled with the cognitive data available through WIHS will enrich our understanding of the role of estrogen receptors in predicting cognitive decline, and potentially inform biomarker selection for screening women who are at higher risk of developing cognitive impairment, especially WLH. This research and training will be performed with Dr. Gretchen N. Neigh, Ph.D., at Virginia Commonwealth University. The training provided will build upon the applicant's technical, computational, and molecular skills, in addition to providing targeted professional development opportunities, and further training in hypothesis-driven project design. Ultimately, this training will prepare the applicant for a future as an independent physician-scientist, investigating factors that impact cognition with aging.