Abstract Alzheimer’s disease is a progressive neurodegenerative disorder leading to profound losses in brain and cognitive abilities. With a projected prevalence of over 14 million by 2050, Alzheimer’s disease represents a growing public health crisis. Research on disease modifying interventions that can slow or prevent Alzheimer’s disease is critically needed, including on modifiable lifestyle behaviors that can act through peripheral systemic mechanisms to enhance resilience against cognitive decline in those with increased risk for Alzheimer’s disease. Recent work has linked aerobic physical activity (PA) to enhanced cerebrovascular function and hippocampal neurogenesis, suggesting pathways to support brain regions vulnerable to Alzheimer’s disease. However, results relating PA and Alzheimer’s disease risk have been mixed, potentially due to differences in how PA is assessed, ranging from self-report to behavioral to physiological measures, as well as inter-individual variation in peripheral systemic physiological responses to PA. There is an urgent need to identify how different PA measures influence cognitive decline in brain aging and preclinical Alzheimer’s risk, and to determine which PA markers best predict differences in susceptibility to Alzheimer’s disease, so brain-based mechanisms can be effectively targeted for PA-based interventions. We plan to evaluate 270 community-dwelling older adults, ages 70 to 84, to obtain baseline physiological measures of cardiorespiratory fitness, behavioral measures of PA from wearable accelerometry, and peripheral blood neurogenic (brain-derived neurotrophic factor) and vascular (endothelial progenitor cells) markers assessed before and after an exercise challenge, together with subjective ratings of recent and lifelong PA. Participants will be evaluated at 18-month intervals to assess trajectories of decline in hippocampal-related memory and frontal-related executive cognitive functions, as well as magnetic resonance imaging scans of brain structure, resting functional connectivity, and white matter integrity and hyperintensity lesion load. The cohort will include those with and without increased preclinical Alzheimer’s disease risk, defined by first-degree Alzheimer’s disease family history and subjective memory concerns. This proposal will address the following specific aims: to investigate how behavioral markers of PA predict longitudinal change in 1) cognitive function and 2) brain structure and functional connectivity in relation to preclinical risk for Alzheimer’s disease; to evaluate how peripheral systemic physiological markers of PA predict longitudinal change in cognition and brain structure and functional connectivity in relation to Alzheimer’s disease risk; and to determine how the peripheral systemic response to aerobic exercise mediates the relation between PA and longitudinal changes in brain and cognition in those with and without increased Alzheimer’s disease risk. By evaluating a no...