Multidimensional physical fitness is associated with reduced dementia risk through proteomic and neuroimaging pathways: a prospective cohort study of the UK Biobank

2026-04-05

AI Summary

This study investigates whether grip strength, cardiorespiratory fitness, and lung function independently influence dementia risk through distinct biological mechanisms. Leveraging the UK Biobank prospective cohort, the research integrates epidemiological analysis, plasma proteomics, brain MRI, and mediation modeling to demonstrate for the first time that multidimensional physical fitness reduces dementia risk via specific yet convergent pathways involving neuroinflammation, neurovascular health, and brain structure. Higher physical fitness was associated with a significantly lower dementia risk (HR 0.50–0.73), and 22–40 dimension-specific plasma proteins predictive of dementia were identified. Mediation analyses revealed that hippocampal volume accounted for 3.7–10.1% of the protective effect, and an estimated 26% of dementia cases were attributable to low physical fitness.

Abstract

Dementia affects over 55 million people worldwide, yet whether distinct domains of physical fitness independently protect against neurodegeneration through shared or divergent biological mechanisms remains unknown. Using the UK Biobank (n = 51,517; 12-year follow-up), we integrated epidemiological, proteomic, and neuroimaging analyses to systematically characterize the multidimensional fitness-dementia relationship. Higher handgrip strength, cardiorespiratory fitness, and pulmonary function were each independently associated with reduced dementia risk (HRs 0.50, 0.62, and 0.73, respectively, for highest vs. lowest tertiles), with stronger associations in women and younger individuals. Plasma proteomic profiling revealed domain-specific molecular signatures--neurofilament light chain predominating for muscular and cardiorespiratory fitness, and inflammatory mediators including GDF15 for pulmonary function--with 22-40 proteins per domain independently predicting dementia, converging on neuroinflammatory and neurovascular pathways. Brain MRI analyses identified hippocampal volume as a significant structural mediator (proportion mediated: 3.7-10.1%), indicating structural preservation as one of multiple mechanistic pathways. Population attributable fraction analyses estimated that suboptimal fitness may account for approximately 26% of dementia cases. These findings reveal that multidimensional physical fitness shapes dementia risk through distinct yet converging neuroinflammatory, neurovascular, and structural brain mechanisms, with implications for life-course prevention.

Problem

• physical fitness
• dementia risk
• neurodegeneration
• biological mechanisms
• multidimensional fitness

Innovation

• multidimensional physical fitness
• proteomic profiling
• neuroimaging mediation
• dementia risk
• neuroinflammatory pathways