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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\u00a0162 European\u2010ancestry UK Biobank participants, Cox models associate OA with higher risks of Alzheimer's disease (AD; hazard ratio: 1.13, 95% confidence interval: 1.04\u20131.22), Parkinson's disease (PD; 1.10, 1.00\u20131.21), and disorders of autonomic nervous system (DANS; 1.36, 1.06\u20131.74), and RA with higher AD risk (1.37, 1.13\u20131.67) (all\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.05), but not incident PD. Mendelian randomization prioritizes a modest protective genetic effect of RA on PD (odds ratio: 0.93, 0.88\u20130.99;\n                    <jats:italic>p<\/jats:italic>\n                    = 0.015), without reverse causation. Transcriptome\u2010wide association and colocalization analyses identify shared RA\u2013PD genes and prioritize Ring Finger Protein 40 (\n                    <jats:italic>RNF40<\/jats:italic>\n                    ). In a collagen\u2010induced arthritis (CIA) and 1\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine (MPTP) mouse model, CIA attenuates dopaminergic injury, whereas systemic\n                    <jats:italic>Rnf40<\/jats:italic>\n                    knockdown alleviates arthritis but exacerbates Parkinsonian pathology. Endogenous RNF40 is induced in arthritic joints but remains stable in midbrain. These cross\u2010layer data define arthritis\u2013neurodegeneration connections and nominate RNF40 as a context\u2010dependent joint\u2013brain candidate linking inflammatory arthritis with dopaminergic vulnerability.\n                  <\/jats:p>","DOI":"10.1002\/advs.76930","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:23:22Z","timestamp":1785936202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Systematic Multi\u2010Level Analyses Decode the Arthritis\u2010Neurodegeneration Axis With In Vivo Validation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1230-6959","authenticated-orcid":false,"given":"Jinwen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital with Nanjing Medical University  Nanjing 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Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0146-921X","authenticated-orcid":false,"given":"Peng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Center For Global Health School of Public Health Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases The First Affiliated Hospital with Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7258-7865","authenticated-orcid":false,"given":"Jun","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital with Nanjing Medical University  Nanjing 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