Observational studies have implied associations between multiple cytokines and cognitive decline, anti-inflammatory drugs however did not yield any protective effects on cognitive decline. We aimed to assess the associations of systemic inflammation, as measured by multiple cytokine and growth factor, with cognitive performance and brain atrophy using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e − 8 and p < 5e − 6) for 41 systemic inflammatory markers were retrieved from a genome-wide association study conducted in 8293 Finnish participants. Summary statistics for gene-outcome associations were obtained for cognitive performance (N = 257,841) and for brain atrophy measures of cerebral cortical surface area and thickness (N = 51,665) and hippocampal volume (N = 33,536). To rule out the heterogeneity in the cognitive performance, we additionally included three domains: the fluid intelligence score (N = 108,818), prospective memory result (N = 111,099), and reaction time (N = 330,069). Main results were computed by inverse-variance weighting; sensitivity analyses taking pleiotropy and invalid instruments into account were performed by using weighted-median estimator, MR-Egger, and MR PRESSO. After correcting for multiple testing using false discovery rate, only genetically predicted (with p < 5e − 6 threshold) per-SD (standard deviation) higher IL-8 was associated with − 0.103 (− 0.155, − 0.051, p_adjusted = 0.004) mm³ smaller hippocampal volume and higher intelligence fluid score [β: 0.103 SD (95% CI: 0.042, 0.165), p_adjusted = 0.041]. Sensitivity analyses generally showed similar results, and no pleiotropic effect, heterogeneity, or possible reverse causation was detected. Our results suggested a possible causal association of high IL-8 levels with better cognitive performance but smaller hippocampal volume among the general healthy population, highlighting the complex role of inflammation in dementia-related phenotypes. Further research is needed to elucidate mechanisms underlying these associations.

观察性研究表明多种细胞因子与认知能力下降之间存在关联，但抗炎药并未对认知能力下降产生任何保护作用。我们的目的是使用双样本孟德尔随机化 (MR) 评估全身性炎症（通过多种细胞因子和生长因子测量）与认知能力和脑萎缩之间的关联。 从对 8293 名芬兰参与者进行的全基因组关联研究中检索到 41 种全身炎症标志物的独立遗传工具（p  < 5e - 8 和p < 5e - 6）。获得了认知表现（N  = 257,841）和大脑皮质表面积和厚度的脑萎缩测量（N  = 51,665) 和海马体积 ( N  = 33,536)。为了排除认知表现的异质性，我们还包括三个领域：流体智力得分（N  = 108,818）、前瞻性记忆结果（N  = 111,099）和反应时间（N  = 330,069）。主要结果通过逆方差加权计算；使用加权中值估计器、MR-Egger 和 MR PRESSO 进行考虑多效性和无效仪器的敏感性分析。在使用错误发现率校正多次测试后，只有基因预测（p  < 5e - 6 阈值）每 SD（标准偏差）较高的 IL-8 与 - 0.103（- 0.155，- 0.051，p_调整后 = 0.004) mm ³海马体体积更小，智力流体评分更高 [ β：0.103 SD（95% CI：0.042，0.165），p_调整后 = 0.041]。敏感性分析通常显示相似的结果，未检测到多效性、异质性或可能的反向因果关系。我们的结果表明，在一般健康人群中，高 IL-8 水平可能与更好的认知表现但更小的海马体体积存在因果关系，突出了炎症在痴呆相关表型中的复杂作用。需要进一步的研究来阐明这些关联背后的机制。