ABSTRACT FOR PROJECT 3 Menopause is a universal experience among women living to midlife, yet our understanding of the immediate and long-term influence of the menopause transition on brain health and cognition is limited. A key component of the Human Connectome-Aging Project (HCP-Aging) has been the ability to collect brain and cognitive data across menopause stages. An enriched sample of 210 women aged 40-59 years provides data on brain structure, function and connectivity at two visits ~ 20 months apart. In the Aging Adult Brain Connectome (AABC) we propose to greatly enhance this dataset by acquiring those same measures at two additional visits in 220 women, for up to 10 years of longitudinal data across all menopause stages. In the Aging Adult Brain Connectome (AABC) we propose to greatly enhance this dataset by acquiring those same measures at two additional visits, for up to 10 years of longitudinal data across all menopause stages. The AABC Menopause Project reflects increased recognition of sex differences in cognitive aging and Alzheimer's disease and related dementias (ADRD), and increased appreciation for the role of menopause and sex steroid hormones like estradiol (E2) on brain health. Our focus is on longitudinal trajectories of change across menopause stages (Aim 1), the role of menopause symptoms (Aim 2), and the vulnerability/resilience factors that influence cognition and brain health at this time in a woman's life (Aim 3). Based on longitudinal studies of cognitive changes across the menopause, we focus on the perimenopause as a likely inflection point in women's brain health. We aim to understand the neural basis of the well-documented memory declines that occur in the perimenopause, and to understand the role of E2 and menopause symptoms on these changes. Recognizing the considerable variability in cognitive complaints in the menopause transition, we also aim to determine the factors that confer vulnerability and resilience to those changes. To this end, we propose to add new measures to AABC to: 1) stage menopause not only using gold-standard bleeding criteria but also a new FDA-approved biomarker (anti-Müllerian hormone; AMH) (Aim 1); 2) assess reported menopausal symptoms, as well as objective measures of vasomotor symptoms (VMS) with ambulatory skin conductance monitors and sleep with actigraphy (Aim 2); and 3) work with other projects and cores to examine vulnerability and resilience factors to influence cognition and brain health (Aim 3). We will also provide key insights into how AD biomarkers change with menopause stage and symptoms, and how AD genetic risk factors influence the trajectory of cognitive and brain changes at midlife. To achieve these goals, we will follow 220 women age 40-59 years of age at two additional neuroimaging visits. We will synergize with other projects and cores to meet the study aims in a cost-effective manner. The ultimate goal of this work is to provide new understanding of how menopause ...