Causal association between rheumatoid arthritis and adecreased risk of Alzheimer's disease A Mendelian randomization study

ObjectiveThis study aimed to examine whether rheumatoid arthritis (RA) is causally associated with Alzheimer's disease (AD).MethodsWe performed atwo-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics datasets from three-stage trans-ethnic genome-wide association studies (GWAS) meta-analyses of 29,880 RA cases and 73,758 controls as exposures and ameta-analysis of 4GWAS datasets consisting of 17,008 AD cases and 37,154 controls of European descent as outcomes.ResultsWe selected 80single nucleotide polymorphisms (SNPs) from GWAS data on RA as instrumental variables (IVs), 60 of which were associated with RA on agenome-wide significance level. The IVW method showed evidence to support an inverse causal association between RA and AD (=-0.039, standard error [SE]=0.017, P=0.021). MR-Egger regression revealed that directional pleiotropy was unlikely to be asource of bias in the results (intercept=0.002; P=0.649). The MR-Egger analysis showed no causal association between RA and AD (=-0.050, SE=0.030, P=0.096). However, the weighted median approach showed that RA and AD were causally linked (=-0.078, SE=0.024, P=0.001). The funnel plot did not show heterogeneity between IVestimates based on the individual variants.ConclusionsThe MR analysis supports that RA was causally associated with areduced risk of AD.