Associations of physical fitness with brain structure, pathology and cognition in cognitively normal older adults

The role of physical fitness in cognitive reserve and brain maintenance remains unclear. We investigated the associations of muscular and aerobic fitness (VO₂max) with markers of brain health and cognition in 353 cognitively unimpaired older adults (mean age = 72.77 ±  7.95 years; 177 females). Muscular fitness comprised handgrip strength, appendicular skeletal muscle mass, and Timed-Up-and-Go performance. Blood biomarkers of Alzheimer's pathology (Aβ_1-42/Aβ_1-40, p-tau₂₁₇, GFAP) and neuroplasticity (BDNF, VEGF, Cathepsin-B), gray matter (GM) volume and thickness, medial temporal lobe (MTL) tau burden ([¹⁸F]PI-2620 PET), white matter hyperintensities, and perivascular spaces (PVS) were assessed. Higher muscular capacity was associated with lower basal ganglia PVS volume, whereas aerobic fitness was related to greater MTL thickness and GM volume. Although fitness did not moderate pathology-cognition associations, VO₂max explained additional variance in verbal memory beyond tau. These findings indicate distinct associations of fitness with brain health, while providing limited support for cognitive reserve. Trial Registration: The study was registered in the German Clinical Trials Register (DRKS00032449; date of registration: 2025-05-07; recruiting ongoing).