Contributions of sex differences in the dynamic change of cognitive reserve across the cognitive spectrum of Alzheimer's disease and estrogen to cognitive reserve in typical aging

About This Grant

PROJECT SUMMARY / ABSTRACT Dr. Carlisle will assess the roles of biological sex and sex hormones on the risk of developing Alzheimer's disease through the lens of cognitive reserve. Females are more likely to develop Alzheimer's disease. Biological sex is the second greatest risk factor for developing Alzheimer's disease only after age. Basic science studies suggest that estradiol-based signaling pathways may be neuroprotective. This creates a disconnect between population and basic science studies, such that females, who have more potentially neuroprotective estrogen exposure compared to males, are more likely to develop Alzheimer's disease. Alzheimer's disease cascades likely start decades before measurable changes in cognition which often coincides with the menopause transition (i.e., perimenopause); therefore, one hypothesis is that changes in ovarian estradiol production during perimenopause occurs at a neurologically vulnerable time (e.g., midlife) for the initiation of early Alzheimer's disease-associated pathology. Females have an episodic memory performance advantage compared to males in early adulthood, therefore may have greater cognitive reserve at baseline. Cognitive reserve is the difference between actual and expected cognitive performance, which can be affected by underlying brain pathology. Despite this advantage, females have a greater memory decline with increasing Alzheimer's disease-related neurodegeneration perhaps due to greater baseline pathology being set up during perimenopause. Additionally, females with greater estrogen exposure may be partially protected from the increased risk of developing Alzheimer's disease due to a delay in the critical period during perimenopause. This project will investigate the dynamic change of cognitive reserve in males and females across the cognitive spectrum of Alzheimer's disease longitudinally (Aim 1). This project will also investigate the contribution of estrogen to differences in cognitive reserve in asymptomatic older adults cross-sectionally (Aim 2) and determine the feasibility and acceptability of performing a comprehensive assessment of the role of estrogen in cognitive reserve in asymptomatic adults with a pilot study starting in midlife (Aim 3). The research aims and training goals will be guided by the excellently assembled team of expert mentors, including Dr. Kerrie Moreau (Training Goal 2: sex differences and sex hormones in aging), Dr. Brianne Bettcher (Training Goal 3: observational studies in Alzheimer's disease and related disorders with cognitive, advanced neuroimaging, and biomarker and genetic outcomes), and Dr. Nichole Carlson (Training Goal 1: collaborating with data modeling in complex longitudinal approaches). This proposal has the potential to: 1) clarify the temporal course of sex differences in cognitive reserve across the cognitive continuum using longitudinal data, and 2) identify biological pathways including sex hormones impacting cognitive reserve even at asymptomatic stages. Moreover, this proposal will prepare Dr. Carlisle along the K-to-R pathway towards being an independent investigator and provide preliminary data for a larger two-timepoint study starting in midlife.