Immunosuppressant Use Mediates Neuroprotection Against Alzheimer's Disease in Rheumatoid Arthritis-A Two-Step Mendelian Randomization and NHANES Study.

OBJECTIVES: To investigate whether immunosuppressant (IS) use contributes to the inverse association between rheumatoid arthritis (RA) and Alzheimer's disease (AD). METHODS: We analyzed NHANES 2011-2014 data, including 217 RA patients aged ≥ 60 years on prescription medications. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST), CERAD, Animal Fluency Test (AFT), and a global cognition z-score (Z-score). Associations between IS use and cognition were evaluated using multivariable linear regression. Additionally, two-sample Mendelian randomization (TSMR) and multivariable MR (MVMR) analyses were performed with GWAS datasets for RA, AD, and IS to examine potential causal effects. RESULTS: We observed that patients with RA using IS performed better in z.DDST (β: 0.335, p = 0.036) and Z-score (β: 0.214, p = 0.032) after adjusting for covariates, with sex-specific differences in cognitive domains. TSMR indicated that genetically predicted RA was associated with lower AD risk (OR: 0.936, p = 4.531E-04), and this effect was largely mediated by IS use. MVMR further validated the independent neuroprotective effect of IS on AD (OR = 0.884, p = 0.003) after adjusting for glucocorticoid and NSAID use, while these other medications showed no significant association with AD risk. CONCLUSIONS: These results suggest that the reduced risk of AD observed in RA patients may be partly related to IS use, highlighting a potential role of IS in improving cognitive function and modulating AD risk.