Feiyue Pan | Searcharxiv

arXiv2026

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

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.

stat.AP↗

arXiv2025

Routine Blood Biomarkers Reveal a Preclinical Continuum of Multiple Myeloma Risk

Multiple myeloma (MM) is preceded by a long preclinical phase spanning decades, yet scalable, non-specialist tools to identify individuals at elevated risk before end-organ damage are lacking. In a prospective analysis of 299,035 cancer-free UK Biobank participants followed for a median of 12.4 years, during which 768 developed incident MM, we conducted a biomarker-wide association scan across 61 routinely measured blood analytes spanning hematological, protein metabolism, renal, and immune categories. Markers of protein dysregulation-elevated total protein, depressed albumin, and a low albumin-to-globulin (A/G) ratio-showed the strongest preclinical associations (hazard ratios 0.61-1.54 per SD), consistent with progressive monoclonal immunoglobulin accumulation and suppression of normal polyclonal synthesis years before diagnosis. These signals were accompanied by indicators of erythropoietic suppression, morphological red cell dysregulation, and a shift toward lower neutrophil and higher lymphocyte fractions, reflecting coordinated perturbations across hematopoietic and immune compartments. Longitudinal trajectory analyses showed that these multi-system deviations emerge more than a decade before diagnosis and intensify as clinical onset approaches. Dose-response modelling revealed pronounced nonlinear associations for protein and erythrocytic markers, with risk concentrated among individuals with extreme values. Incorporating significant biomarkers into a clinical risk model improved 10-year MM discrimination from a C-index of 0.684 to 0.744, with the high-risk decile accumulating 0.79% cumulative incidence versus 0.47% under the clinical model alone. These findings provide a practical framework for biomarker-guided MM risk stratification and targeted surveillance using routinely available clinical tests.

stat.AP↗