Causal effects of circulating cytokine concentrations on risk of Alzheimer’s disease and cognitive function

BACKGROUND: There is considerable evidence suggesting a role of neuroinflammation in the pathogenesis of Alzheimer’s disease. Establishing causality 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 Alzheimer’s disease risk and cognitive function. We employed genetic variants from the largest publicly available genome-wide association studies (GWASs) of cytokine concentrations (N = 8,293), Alzheimer’s disease (71,880 cases/383,378 controls), prospective memory (N = 152,605 to 462,302), reaction time (N = 454,157 to 459,523) and fluid intelligence (N = 149,051). RESULTS: Evidence 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 Alzheimer’s disease. There was weak evidence of a causal effect 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 Alzheimer’s disease risk. A 1 SD increase in concentration of Eotaxin (IVW: OR = 1.05 95% CI: 0.98 to 1.13, p = 0.14), IL-8 (OR = 1.21 95% CI: 1.07 to 1.37, p = 0.003) and MCP1 (OR = 1.07 95% CI: 1.03 to 1.13, p = 0.003) were associated with lower fluid intelligence, and IL-4 (OR = 0.86 95%CI: 0.79 to 0.98, p = 0.02) with higher. CONCLUSIONS: Our findings suggest a causal role of cytokines in the pathogenesis of Alzheimer’s disease and fluid intelligence.