Exploring the cognitive effects of arthritis: A Mendelian randomization study and cross-sectional analysis of NHANES data

This study aimed to investigate the relationship between cognitive performance and the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA), emphasizing the role of plasma metabolites and proteins. Using National Health and Nutrition Examination Survey 2011 to 2014 data, cognitive functions of participants aged >60 years were evaluated, examining their correlation with OA and RA. Covariates, including demographics and health-related factors, were included. Genetic causality was determined using Mendelian randomization with single-nucleotide polymorphisms from the UK Biobank and other datasets. Linkage disequilibrium score regression and colocalization analyses were performed to validate genetic correlations and identify shared genetic variants. Cognitive performance was assessed in 387 and 237 OA and RA patients, respectively, compared with 1569 controls. OA patients had significantly lower Consortium to Establish a Registry for Alzheimer's Disease-4 cognitive scores (odds ratio [OR]: 0.962, P = .001), while RA patients had lower digit symbol substitution test scores (OR: 0.980, P = .001). Mendelian randomization revealed a negative causal association between cognitive performance and OA (OR: 0.767, P = .001) and RA (OR: 0.712, P = .006). Plasma components, including bone sialoprotein 2, NKP44, and the metabolite X-11478, were causally linked to cognitive performance. Mediation analysis identified mediators, including FGR and 6CKine. Linkage disequilibrium score regression revealed a genetic correlation between cognitive performance and OA and RA, with colocalization analysis identifying shared genetic factors. GDF5 and TRAIP were associated with OA, and EHMT2 with RA. Cognitive factors, influenced by plasma components, may influence OA and RA onset. This relationship highlights the need for integrated interventions targeting cognitive function and joint health.