. In this study we identify a unique signature protein and metabolic biomarker panel for those who improve in cognition and those who decline, assessed by the Montreal Cognitive Assessment (MoCA). We investigate a discovery cohort of Brain in Motion participants involving a quasi-experimental aerobic exercise intervention study and analyze blood plasma before and after a six-month aerobic exercise intervention and 5 years later. We relate the differentially expressed proteins and metabolites to subjective sleep quality measures and fitness level. This study informs on the differences in the plasma of those who decline and those who improve in cognition, identifying pathways that are of importance for preventing cognitive decline.