PROJECT SUMMARY No effective treatments are available to reduce the consequences of pathologic Alzheimer's disease (AD) and related pathologies on cognitive decline and AD dementia in our aging population. While the link between physical activity and cognition is well-documented, the molecular mechanisms underlying its cognitive benefit have not yet been identified. This knowledge gap is a barrier for physical activity interventions to prevent AD and related dementias (ADRD) and cognitive decline in old age. This proposed supplement will apply the large-scale muscle proteomics platform developed by MoTrPAC project to muscle samples from deceased well-characterized older participants of the Memory and Aging Project at Rush Alzheimer's Disease Center to discover muscle proteins impacted by physical activity in older adults and identify proteins which may link a higher level of physical activity with better cognition and reduced odds of dementia prior to death. The proposed project will leverage available data and biospecimens from Memory and Aging Project including annual cognitive and motor testing, self-report medical history and physical activity. Quantitative physical activity metrics are extracted from multiday recordings from a wrist-worn monitor during everyday living. Brain indices of ADRD pathologies are collected from decedents undergoing autopsy and frozen quadriceps muscle is available. The project has two objectives: 1) Quantify the proteome in postmortem quadriceps muscle samples (N = 500) from well-characterized older adults. Apply the large-scale muscle proteomics platform developed by MoTrPAC project for relative quantification of ~8,000 proteins in quadriceps muscle samples. 2) Identify muscle proteins which link a higher level of physical activity with better cognition and reduced odds of dementia in older adults. A multistage analysis will be used to identify muscle proteins related to a) physical activity and b) cognition proximate to death. Then analyzing proteins related to both phenotypes, we will identify proteins that link physical activity with better cognition.