PROJECT SUMMARY Pulsatility is a measure of fluctuations in flow over the duration of a cardiac cycle. Increases in pulsatility in the cerebral vessels with advancing age have been linked to structural damage in the brain. Cerebral pulsatility is elevated in patients with vascular dementia and Alzheimer’s disease. The goal of our research is to understand age-related changes in cerebral blood flow regulation, how this impacts global and regional perfusion of the brain, and determine successful interventions for improving cerebral blood flow control. In order to understand age-related changes, it is critical to take into account sex differences and how the trajectory of these changes may differ between men and women. Our preliminary data shows that the rate of increase in cerebral pulsatility over the human lifespan is greater in women compared with men. This work suggests that women may be more vulnerable to changes in cerebral pulsatility with advancing age. In the parent grant, we have state-of-the-art neuroimaging tools available to assess cerebral pulsatility in multiple cerebral vessels in a large cohort of middle- aged and older adults. Therefore, the objectives of this supplement application are to leverage existing MRI scans to investigate biological sex differences in cerebral pulsatility. Our hypothesis is that there are sex differences in cerebral pulsatility that impact brain health. Importantly, this project will be the first to investigate sex differences in cerebral pulsatility and determine associations with neurobiological markers of brain health. Aim 1 will determine if there are sex differences in cerebral pulsatility in multiple intracranial arteries. Aim 2 will explore the influence of vascular risk factors and physical activity on cerebral pulsatility. Aim 3 will determine the impact of cerebral pulsatility on neurobiological markers of brain health and Alzheimer’s disease and then determine if these relationships are sex-specific. This project will provide essential information to determine sex differences in cerebral pulsatility. It will also explore the influence of physical activity and other vascular risk factors, and determine potential sex-specific associations with neurobiological markers of brain health that are important for the risk of Alzheimer’s disease and dementia. To achieve these aims, we will employ innovative MRI analysis from existing neuroimaging scans in a large cohort of middle-aged and older adults. This application aligns with recent recommendations published by the NIH emphasizing the need for human studies to identify and confirm biomarkers of vascular processes related to cognitive impairment. Upon completion, we will understand whether sex differences in cerebral pulsatility are contributing to a greater risk for Alzheimer’s disease and related dementias.