Project Summary Despite the over-representation of women in the Alzheimer’s disease population, the influence that sex and sex steroid hormones have on the aging brain remains understudied. 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 17-estradiol and progesterone. For many women, this endocrine change is accompanied by self-reported decrements in memory and attention, or “menopause fog”. 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. The degree to which female reproductive aging leads to changes in human macrostructural brain morphology, intrinsic brain network connectivity, and the neural circuits underlying higher-order cognition represents a significant knowledge gap that has yet to be adequately examined. This project will probe the effects of reproductive aging on the brain in healthy midlife women (N=90, ages 45–55), investigating the endocrine basis of neural and cognitive 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. This project will build on the existing menopause literature by applying state-of-the-art computational techniques to extend beyond our current understanding of fairly coarse regional differences in brain activity and morphology by menopause status. In Aim 1, I will 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. In Aim 2, I will 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 Aim 3, I will determine the effects of reproductive aging on neural mechanisms of selective attention, including the ability to suppress neural processing of irrelevant information, with the goal of elucidating the neural underpinnings of common cognitive complaints during menopause. This project will clarify the endocrine basis of age-related neural and cognitive changes, a severely understudied area in cognitive neuroscience with clear implicati...