Mendelian Randomization Analysis of the Relationship Between Immune-Related Diseases and Alzheimer’s Disease

Dong-Hong Huang,1,* Yue-ling Zhang,1,* Sheng-Liang Shi,1 Tian-Jia Liang,2 Jun-jian Chen,3 Guo-Qiao Li,4 Zhao-De Chen2 1Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, 530000, People’s Republic of China; 2Department of Rehabilitation, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, People’s Republic of China; 3Department of Respiratory, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, People’s Republic of China; 4Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Sheng-Liang Shi, Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, No. 166, University East Road, Xixiangtang District, Nanning, Guangxi, 530000, People’s Republic of China, Tel/Fax +86-07713278031, Email [email protected] Tian-Jia Liang, Department of Rehabilitation, The Second Affiliated Hospital of Guangxi Medical University, No. 166, University East Road, Xixiangtang District, Guangxi, 530000, People’s Republic of China, Email [email protected]: Emerging evidence suggests a genetic link between immune-related diseases and Alzheimer’s disease (AD), though the underlying mechanisms remain unclear. This Mendelian randomization (MR) study investigates the genetic relationship between six immune-related diseases—type 1 diabetes (T1DM), systemic lupus erythematosus (SLE), asthma, myasthenia gravis (MG), endometriosis, and idiopathic thrombocytopenic purpura (ITP)—and AD.Methods: Summary-level data were obtained from publicly available genome-wide association studies (GWAS) for the six immune-related diseases and AD. MR-estimation was conducted utilizing the inverse variance weighted (IVW), MR-Egger, and WM methods. Additionally, sensitivity analyses were performed, encompassing Cochran’s Q test, MR-Egger intercept, MR-Pleiotropy residual sum and outlier (MR-PRESSO) method, leave-one-out analysis, and funnel plots.Results: A statistically significant association was identified between asthma and a slightly lower risk of AD (odds ratio [OR] = 0.996, 95% CI: 0.994– 0.997, P = 0.001); however, the effect size was negligible and likely lacks clinical significance. No significant genetic associations were found between T1DM, SLE, MG, endometriosis, or ITP and AD. Reverse MR analyses indicated no evidence of reverse causality from AD to these immune-related conditions.Conclusion: Although a nominal association was observed, this MR analysis does not support a causal relationship between genetic liability to asthma and Alzheimer’s disease. This relationship underscores the specificity of the association, as no causal connections were found between other studied immune-related diseases conditions—T1DM, SLE, MG, endometriosis, and ITP—and AD.Keywords: immune-related diseases, Alzheimer’s disease, causality, Mendelian, randomization