Genetically predicted levels of circulating cytokines and risk of Alzheimer's and Parkinson's disease: evidence from complementary genetic methods

Abstract

Background Alzheimer's disease (AD) and Parkinson's disease (PD) are the top two common neurodegenerative diseases. In recent years, the role of cytokines-related neuroinflammatory response in the pathogenesis of AD/PD has received increasing attention. This study aims to investigate the relationship between genetically determined cytokines and the risk of AD/PD.Methods Four systematic univariable Mendelian randomizations (MR) approaches were adopted to assess the causal effect of cytokines on AD/PD and their robustness, including inverse-variance weighted (IVW), weighted-median estimator (WME), robust adjusted profile score (RAPS), and wald ratio (WRO) methods. Furthermore, multivariate MR (MVMR) with Bayesian model averaging (MR-BMA) was performed to prioritize the cytokine combinations that may be on the AD/PD causal pathway. Besides, we used the standard IVW MVMR to re-estimate the causal effect and confidence interval of each cytokine in the top 10 models screened by MR-BMA. Bidirectional MR analysis was additionally performed to detect the causal directionality. Finally, results generated by univariate MR and MR-BMA methods were combined.Results Univariable MR (IVW) analysis indicated genetically determined higher levels of macrophage inflammatory protein-1 beta (MIP1b) were positively associated with both AD and PD [odds ratios (ORs) and 95% confidence intervals (95%CIs) were 1.05 (1.01–1.09) and 1.06 (1.02–1.10)]. Besides, Interleukin (IL) IL16 was positively associated with PD [OR (95%CI): 1.09 (1.01–1.18)]. However, IL2 receptor alpha (IL2ra) was negatively associated with AD [OR (95%CI): 0.92 (0.86–0.98)]. Particularly, MR-BMA analysis corroborated that MIP1b was the top priority risk factor for both AD and PD [posterior probability (marginal inclusion probability): 0.212 (0.190) and 0.509 (0.782)]. In addition, standard IVW MVMR detected that the genetical positive effect of MIP1b on both AD and PD was still significant. The relationship between MIP1b and PD was further replicated by FinnGen summary-level dataset. Finally, the results of bidirectional MR showed neither AD nor PD could modify the level of MIP1b.Conclusions Genetic predisposition to elevated circulating levels of MIP1b was associated with a higher risk of both AD and PD. In addition, MIP1b was screened as the most prioritized cytokine-related risk factor. Whether targeting MIP1b or its pathways could lower the AD/PD incidence requires future functional studies.