Longitudinal Proteomic Profiling of Cognition across an Aerobic Exercise Intervention

The physiological basis of cognitive decline remains largely uncharacterized. We identified a protein panel signature, in living humans, that correlates to improvement in neurocognition over a period of 5 years. Our signature is composed of complement proteins, coagulation cascade, and extracellular matrix regulators. In our cohort, SERPINF1 is associated with greater maximal oxygen uptake after an aerobic exercise intervention. Sleep quality is also a key factor in relation to inter-alpha-trypsin inhibitor heavy chain H2, which was associated with greater sleep efficiency. Additionally, we validate that the coagulation profile of decliners’ plasma contains procoagulant agonists, leading to greater platelet activation. ANN NEUROL 2025;97:1007–1018.