This study aimed to examine whether rheumatoid arthritis (RA) is causally associated with Alzheimer's disease (AD).
We performed a two-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 a meta-analysis of 4 GWAS datasets consisting of 17,008 AD cases and 37,154 controls of European descent as outcomes.
We selected 80 single nucleotide polymorphisms (SNPs) from GWAS data on RA as instrumental variables (IVs), 60 of which were associated with RA on a genome-wide significance level. The IVW method showed evidence to support an inverse causal association between RA and AD (β = -0.039, standard error [SE] = 0.017, P = 0.021). MR-Egger regression revealed that directional pleiotropy was unlikely to be a source of bias in the results (intercept = 0.002; P = 0.649). The MR-Egger analysis showed no causal association between RA and AD (β = -0.050, SE = 0.030, P = 0.096). However, the weighted median approach showed that RA and AD were causally linked (β = -0.078, SE = 0.024, P = 0.001). The funnel plot did not show heterogeneity between IV estimates based on the individual variants.
The MR analysis supports that RA was causally associated with a reduced risk of AD.