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

TL;DR

This study shows that various aspects of physical fitness independently reduce dementia risk through distinct biological pathways, including neuroinflammation, neurovascular health, and brain structure, based on a 12-year UK Biobank cohort analysis.

Contribution

It systematically links multidimensional physical fitness to dementia risk and identifies specific proteomic and neuroimaging mediators, revealing multiple mechanistic pathways.

Findings

Higher fitness levels are associated with lower dementia risk.

Proteomic signatures differ across fitness domains, involving neuroinflammatory and neurovascular proteins.

Hippocampal volume partially mediates the fitness-dementia relationship.

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.