Systematic Multi-Level Analyses Decode the Arthritis-Neurodegeneration Axis With In Vivo Validation

Arthritis may influence neurodegenerative risk, but directionality and mediators remain unclear. This study integrates population survival analysis, Mendelian randomization, transcriptomic mapping, and mouse perturbation to map osteoarthritis (OA)/rheumatoid arthritis (RA) links with five neurodegenerative outcomes and prioritize mediators. In 310 162 European-ancestry UK Biobank participants, Cox models associate OA with higher risks of Alzheimer's disease (AD; hazard ratio: 1.13, 95% confidence interval: 1.04-1.22), Parkinson's disease (PD; 1.10, 1.00-1.21), and disorders of autonomic nervous system (DANS; 1.36, 1.06-1.74), and RA with higher AD risk (1.37, 1.13-1.67) (all p < 0.05), but not incident PD. Mendelian randomization prioritizes a modest protective genetic effect of RA on PD (odds ratio: 0.93, 0.88-0.99; p = 0.015), without reverse causation. Transcriptome-wide association and colocalization analyses identify shared RA-PD genes and prioritize Ring Finger Protein 40 (RNF40). In a collagen-induced arthritis (CIA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, CIA attenuates dopaminergic injury, whereas systemic Rnf40 knockdown alleviates arthritis but exacerbates Parkinsonian pathology. Endogenous RNF40 is induced in arthritic joints but remains stable in midbrain. These cross-layer data define arthritis-neurodegeneration connections and nominate RNF40 as a context-dependent joint-brain candidate linking inflammatory arthritis with dopaminergic vulnerability.