Physical fitness supports brain maintenance and cognitive reserve in cognitively normal aging: a cross-sectional examination

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Abstract Background Preserving cognitive and brain health is central for healthy aging. Cognitive reserve (CR) and brain maintenance (BM) support resilience against age- and disease-related cognitive decline. Physical fitness represents a plausible pathway to both CR and BM, yet the underlying neurobiological mechanisms remain insufficiently understood. This study examined how fitness relates to Alzheimer’s pathology and whether it moderates or mediates the pathology–cognition relationship. Methods Data were obtained from 345 cognitively unimpaired older adults (mean age = 73.11 ± 8.03 years; 177 females) participating in the ongoing SFB1436 study. We assessed global cognition and delayed verbal memory performance, aerobic fitness (VO₂max), and muscular capacity. Blood biomarkers included plasma Aβ₁₋₄₂/Aβ₁₋₄₀, p-tau217, and GFAP (glial fibrillary acidic protein), and serum BDNF (brain-derived neurotrophic factor), VEGF (vascular endothelial growth factor), and Cathepsin-B. Neuroimaging measures comprised medial temporal lobe (MTL) tau burden ([¹⁸F]PI-2620 PET), MRI-derived hippocampal volumes, white matter hyperintensities, perivascular spaces (PVS) in basal ganglia (BG) and centrum semiovale, gray matter volume (GMV), and MTL thickness. To examine BM, we tested associations between fitness and brain pathology. To examine CR, we conducted moderation analyses assessing whether fitness attenuated the negative impact of pathology on cognition. Mediation analyses further evaluated whether hippocampal volume, total GMV, or MTL thickness mediated a potential association between fitness and cognition. All models controlled for age and sex (and education in mediation analyses), and multiple comparisons were FDR-corrected. Results Physical fitness was not related to cognitive performance. Higher muscular capacity was associated with lower BG PVS volumes, while higher aerobic fitness was related to higher MTL thickness and total GMV. Elevated MTL tau burden was associated with poorer verbal memory performance. Although physical fitness did not significantly moderate the tau–memory relationship, model comparison provided weak evidence for CR effects (p = .015). Conclusion Muscular capacity was linked to lower BG PVS volumes, supporting resistance against pathology, while aerobic fitness related to preserved cortical integrity and tended to act as a CR proxy against MTL tau pathology. Physical fitness may support cerebrovascular and glymphatic function, thereby promoting cognitive resilience and extending healthspan by sustaining functional brain health and mitigating tau-related cognitive decline. Trial Registration The study was retrospectively registered in the German Clinical Trials Register (DRKS00032449; date of registration: 2025-05-07; recruiting ongoing).

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