Blood neurodegeneration biomarkers and the muscle–brain axis in older adults: physical performance as a functional mediator of cognition

INTRODUCTION: Age-related neuromuscular decline may reflect the muscle-brain axis linking neurodegeneration to cognitive impairment. This study examines whether physical performance mediates associations between blood neurodegeneration biomarkers and cognition, and whether cognitive reserve modulates these relationships. METHODS: We conducted a cross-sectional analysis of 206 outpatients aged ≥65 years. Physical performance was assessed via handgrip strength, 6-minute walk test, and Short Physical Performance Battery. Cognitive function was evaluated using MMSE, MoCA, verbal fluencies, and memory tasks. Plasma levels of neurofilament light chain (NfL), phosphorylated tau (p-tau181), and GFAP were measured using Simoa assays. Principal component analyses were used to derive latent physical and cognitive performance scores. Structural equation modeling assessed direct and indirect associations, with moderation by cognitive reserve (CRIq). RESULTS: Higher NfL levels were associated with poorer physical performance (β = -0.24, p = 0.004) and showed associations with worse cognitive outcomes both directly and indirectly (β = -0.09, p = 0.010). P-tau181 was directly associated to cognitive performance (β = -0.19, p = 0.020), while GFAP showed no significant associations. Exploratory stratified analyses suggested that potential mediation by physical function was prominent among individuals with lower CRIq scores, whereas in those with higher reserve, direct effects of p-tau181 on cognition predominated. CONCLUSIONS: Blood neurodegeneration biomarkers show complex associations with cognition that involve direct and physical performance-related pathways. Our findings suggest that physical performance may serve as an early marker and therapeutic target in neurodegenerative aging, particularly in vulnerable populations, though longitudinal studies are needed to establish temporal relationships. TRIAL REGISTRATION: Not applicable.