Project Summary Relative to males, females exhibit greater cognitive decline and are more severely impacted by age-related disease (e.g., Alzheimer’s disease (AD)). The impact of AD risk factors such as the apolipoprotein E4 (ApoE4) allele, accumulation of AD biomarkers, and cognitive impairment with AD is more pronounced in females and does not simply reflect their greater longevity. The reasons for these sex differences remains unclear, thus, it is important to probe the biological underpinnings of sex distinctions in the aging brain. Menopause may contribute to the disproportionate impact of aging on females as it is accompanied by a large decrease in estrogens, which have neuroprotective effects on brain health and cognition. Notably, AD pathology begins to develop decades before clinical symptom onset, and this preclinical phase of AD overlaps with the menopausal transition during mid-life (late 40s-early 50s). Thus, the depletion of estrogen with menopause may increase female susceptibility to AD pathogenesis. In fact, changes in reproductive hormones have been associated with increased risk for developing AD and poor memory function. The medial temporal lobe (MTL) network, which is important for memory, is dysfunctional in aging and AD. Deficits in emotional memory are observed with the menopausal transition and early development of AD pathology. Moreover, early changes in emotional memory brain networks, including the MTL, have been discovered in preclinical AD and are the first to accumulate AD pathology. Given substantial evidence of interactions between menopause and early AD, interrogating the linkage between reproductive aging and AD risk is critical for uncovering sex-specific factors involved in age-related disease and creating novel approaches to treatment or prevention. However, work on the impact of menopause in aging females is lacking, especially in the context of genetic risk for AD. To address these gaps, the proposed project will examine the effect of estrogen decline with menopause on MTL network dynamics and emotional memory in cognitively normal females at risk for AD (e.g., ApoE4+). Aim 1 will establish the relationship between estrogen levels and AD risk in aging females, Aim 2 will quantify the impact of estrogen on MTL network connectivity in aging females at risk for AD, and Aim 3 will determine the effect of estrogen on MTL activation and emotional memory in females at risk for AD. Together, the proposed work will provide important new insight into the biological mechanisms underlying sex differences in AD. Examining the impact of menopause in cognitively normal aging during the same timeframe that AD pathology begins could provide a novel approach towards the early detection of AD. These aims will offer many training opportunities for the applicant, who will gain proficiency in complex neuroimaging analyses, enhanced statistical skills, application of aging research towards disease states (e.g., AD), and valuable mentorship experience. The training opportunities facilitated by this work will accelerate the applicant’s transition to an independent career focused on sex differences in aging outcomes.

Project Narrative Alzheimer’s disease (AD) is significantly more common in females than males, and females carry greater risk for developing AD; however, the reason for these sex differences remains unknown. The proposed project aims to explore the interaction between the menopausal transition and accompanied decreases in estrogen on brain networks supporting memory in females at risk for AD. The insight gained from this research will increase our understanding of the neurobiological and neuroendocrine processes underlying sex differences in AD and will aid the early detection of AD, which is crucial for intervening and slowing disease progression.