Elucidating the role of endocrine aging as a risk factor for Alzheimer's Disease

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Project Summary Women constitute two-thirds of the Alzheimer’s disease (AD) population. While the sex-specific biological mechanisms underlying women’s increased prevalence are unclear, accumulating evidence points to menopause as a neurological transition state that may influence AD risk. Over the last quarter century, the vast majority of brain imaging studies have studied the neural basis of age-related cognitive decline in adults aged 65 and older. This convention overlooks one of the most significant neuroendocrine changes in a woman’s life— the transition to menopause—and leaves a gap in our understanding of the aging brain during the critical midlife years. The menopausal transition is marked by a sweeping decline in the production of sex hormones—up to 90% in the case of 17b-estradiol and progesterone. Animal studies provide powerful evidence that estradiol and progesterone play a neuroprotective role in brain regions vulnerable to neurodegeneration, including the prefrontal cortex and medial temporal lobes. However, the degree to which female reproductive aging leads to changes in human brain morphology, intrinsic brain network connectivity, and susceptibility to increased AD prevalence represents a significant knowledge gap that has yet to be adequately examined. This proposal will establish whether the decline in sex steroid hormones over the menopausal transition relates to vulnerability in brain circuits implicated in AD. In the F99 phase (Aim 1), I will probe the effects of reproductive aging on the brain in healthy women (N=90, ages 45–55), investigating the endocrine basis of neural aging in midlife. The well-characterized sample is enriched to include a balanced distribution of pre, peri, and post-menopausal women across a limited age range in order to isolate the effects of reproductive aging from chronological aging. I will first determine how the depletion of sex hormones in midlife alters large-scale functional brain networks using resting-state fMRI and computational approaches from complex systems analysis. I will then use high- resolution anatomical imaging of the hippocampus and surrounding medial temporal lobe to determine whether the depletion of sex hormones impacts specific hippocampal subfields (CA1-3, dentate gyrus, subiculum) and entorhinal, perirhinal, and parahippocampal cortices, regions enriched with sex hormone receptors. In the K00 phase (Aim 2), I will take the skills and insights gained from the F99 phase, including fundamental training in neuroendocrinology and brain imaging, and use them to establish the relationship between female reproductive aging and pathological AD biomarkers (b-amyloid, tau). To do this, I will leverage two large community cohorts (N~620, 60% female) that provide relevant hormonal, cognitive, and molecular positron emission tomography (PET) data from midlife subjects (ages 40-65) and build a neuroendocrine model of AD risk. Together, this proposal will identify the role menopause plays in contributing to female-specific vulnerability to Alzheimer’s disease, a severely understudied area in cognitive neuroscience with clear implications for women’s health.