Causal effects of circulating cytokine concentrations on risk of Alzheimers disease: A bidirectional two-sample Mendelian randomization study

Abstract

BackgroundThere is considerable interest in the role of neuroinflammation in the pathogenesis of Alzheimers disease. Evidence from observational studies suggests an association between cytokine concentrations and Alzheimers disease. However, establishing a causal role of cytokine concentrations on risk of Alzheimers disease is challenging due to bias from reverse causation and residual confounding. MethodsWe used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimers disease and vice versa, employing genetic variants associated with cytokine concentrations (N=8,293) and Alzheimers disease (71,880 cases / 383,378 controls) from the largest non-overlapping genome-wide association studies (GWAS) of European ancestry. ResultsThere was weak evidence to suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR= 1.09 95%CI: 1.01 to 1.19, p=0.03) increased risk of Alzheimers disease. There was also weak evidence of a causal effect of 1 SD increase in levels of MIP-1b (CCL4) (OR=1.04 95%CI: 0.99 to 1.09, p=0.08), Eotaxin (OR=1.08 95%CI: 0.99 to 1.17, p =0.10), GROa (CXCL1) (OR=1.04 95%CI: 0.99 to 1.10, p=0.15), MIG (CXCL9) (OR=1.17 95%CI: 0.97 to 1.41, p=0.10), IL-8 (Wald Ratio: OR=1.21 95%CI: 0.97 to 1.51, p=0.09) and IL-2 (Wald Ratio: OR=1.21 95%CI: 0.94 to 1.56, p=0.14) on greater risk of Alzheimers disease. There was little evidence of a causal effect of genetic liability to Alzheimers disease on circulating cytokine concentrations. ConclusionsOur study provides some evidence supporting a causal role of cytokines in the pathogenesis of Alzheimers disease. However, more studies are needed to elucidate the specific mechanistic pathways via which cytokines alter the risk of Alzheimers disease.