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. 2025 Sep 24:18:6063-6077.
doi: 10.2147/JMDH.S533723. eCollection 2025.

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 Chen  2
Affiliations

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

Dong-Hong Huang et al. J Multidiscip Healthc. .

Abstract

Objective: 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: Alzheimer’s disease; Mendelian; causality; immune-related diseases; randomization.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flowchart illustrating the design of MR analysis for T1DM, SLE, asthma, MG, endometriosis, ITP and AD.
Figure 2
Figure 2
MR analysis of T1DM and AD. (A) SNP effect on T1DM; (B) MR leave-one-out sensitivity analysis. (C) MR-Egger.
Figure 3
Figure 3
MR analysis of SLE and AD. (A) SNP effect on SLE; (B) MR leave-one-out sensitivity analysis; (C) MR-Egger.
Figure 4
Figure 4
MR analysis of asthma and AD. (A) SNP effect on Asthma; (B) MR leave-one-out sensitivity analysis; (C) MR-Egger.
Figure 5
Figure 5
MR analysis of MG and AD. (A) SNP effect on MG; (B) MR leave-one-out sensitivity analysis; (C) MR-Egger.
Figure 6
Figure 6
MR analysis of endometriosis and AD. (A) SNP effect on endometriosis; (B) MR leave-one-out sensitivity analysis; (C) MR-Egger.
Figure 7
Figure 7
MR analysis of ITP and AD. (A) SNP effect on ITP; (B) MR leave-one-out sensitivity analysis; (C) MR-Egger.
See this image and copyright information in PMC

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