Causal relationships between type 1 diabetes mellitus and Alzheimer's disease and Parkinson's disease: a bidirectional two-sample Mendelian randomization study

Abstract

Background: Previous compelling evidence suggests an association between Type 2 diabetes (T2D) and neurodegenerative diseases. However, it remains uncertain whether Type 1 diabetes mellitus (T1DM) exerts a causal influence on the risk of Alzheimer's disease (AD) and Parkinson's disease (PD). Consequently, this study employed a bidirectional two-sample Mendelian Randomization (MR) approach to investigate the causal relationship between T1DM and the genetic susceptibility to AD and PD.

Methods: We utilized large-scale cohorts derived from publicly available genome-wide association study datasets involving European populations to perform MR analyses. The primary analytical method employed was the inverse-variance weighted (IVW) approach. Furthermore, sensitivity analyses, including assessments of heterogeneity and horizontal pleiotropy, were carried out using Cochran's Q, MR-Egger intercept, and MR-PRESSO tests to enhance the robustness of our conclusions.

Results: Using the IVW-based method, the MR analysis indicated no significant association between genetically determined T1DM and AD (OR = 0.984, 95% CI: 0.958-1.011, p = 0.247). Conversely, T1DM appeared to be associated with a reduced risk of genetic susceptibility to PD (IVW: OR = 0.958, 95% CI: 0.928-0.989, p = 0.001). In the reverse direction, no evidence of reverse causality was observed between AD (OR = 1.010, 95% CI: 0.911-1.116, p = 0.881) or PD (OR = 1.164, 95% CI: 0.686-2.025, p = 0.5202) and T1DM. Additionally, our analysis found no indications of the results being influenced by horizontal pleiotropy.

Conclusion: This MR study reveals that T1DM is associated with a reduced genetic susceptibility to PD, whereas no significant genetic susceptibility is observed between T1DM and AD. These findings suggest that T1DM may have a distinct role in the development of neurodegenerative diseases compared to T2D. Further investigations are warranted to elucidate the underlying mechanisms and provide a more comprehensive understanding of this relationship.

Keywords: Alzheimer’s disease; Mendelian randomization; Parkinson’s disease; Type 1 diabetes mellitus.