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

Background: There 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. Methods: We 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. Results: There 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. Conclusions: Our 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.