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.

中文翻译：

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循环细胞因子浓度对阿尔茨海默病风险和认知功能的因果影响

背景

有大量证据表明神经炎症在阿尔茨海默氏病的发病机制中发挥作用。由于反向因果关系和残余混杂的偏差，建立因果关系具有挑战性。

方法

我们使用两个样本的 MR 来探索循环细胞因子浓度对阿尔茨海默病风险和认知功能的因果影响。我们采用了来自最大的公开全基因组关联研究 (GWAS) 的遗传变异，这些研究涉及细胞因子浓度 (N = 8,293)、阿尔茨海默病 (71,880 例病例/383,378 对照)、前瞻性记忆 (N = 152,605 至 462,302)、反应时间 (N = 454,157 至 459,523）和流体智力（N = 149,051）。

结果

有证据表明，CTACK (CCL27) 水平每增加 1 个标准差 (SD)（OR = 1.09 95%CI：1.01 至 1.19，p = 0.03），患阿尔茨海默病的风险就会增加。有微弱证据表明 MIP-1b (CCL4)（OR = 1.04 95% CI：0.99 至 1.09，p = 0.08）、嗜酸细胞趋化因子（OR = 1.08 95% CI：0.99 至 1.17，p = 0.10）、 GROa (CXCL1)（OR = 1.04 95% CI：0.99 至 1.10，p = 0.15）、MIG (CXCL9)（OR = 1.17 95% CI：0.97 至 1.41，p = 0.10）、IL-8（Wald 比：OR = 1.21 95% CI：0.97 至 1.51，p = 0.09）和 IL-2（Wald 比：OR = 1.21 95% CI：0.94 至 1.56，p = 0.14）对阿尔茨海默病风险的影响。Eotaxin 浓度增加 1 SD（IVW：OR = 1.05 95% CI：0.98 至 1.13，p = 0.14）、IL-8（OR = 1.21 95% CI：1.07 至 1.37，p = 0.003）和 MCP1（OR = 1.07 95% CI：1.03 至 1.13，p = 0.003）与较低的液体智力相关，而 IL-4（OR = 0.86 95% CI：0.79 至 0.98，p = 0.02）则与较高的液体智力相关。

结论

我们的研究结果表明细胞因子在阿尔茨海默病和流体智力的发病机制中具有因果作用。