Cathepsin in Alzheimer's Disease, Parkinson's Disease and Dementia with Lewy Bodies: Mendelian Randomization Study

Abstract

Abstract Background Observational studies indicate a strong association between most neurodegenerative disorders and cathepsin, although the causative link remains unclear. Methods This research utilized Mendelian Randomization (MR) with genetic markers linked to cathepsins as instrumental variables, and analyzed public Genome-Wide Association Studies (GWASs) summary data of individuals with European ancestry for Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) as the outcomes. The study applied the inverse variance-weighted (IVW) method to assess the causal effects of cathepsins on AD, PD, and DLB. Several sensitivity analyses and a heterogeneity test were conducted to evaluate the effectiveness of the results. Confounding variables were accounted for using multivariable MR (MVMR). Additionally, reverse MR research was done to improve forward MR analysis. Lastly, we utilize Bayesian Weighted MR (BWMR) to further validate the robustness of the results. Results The MR investigation found an association between cathepsin H and AD and DLB risk. However, there was a negative correlation between PD risk and cathepsin B levels. Effect estimates in MVMR and BWMR analyses with cathepsins as variables remained constant. According to reverse MR analysis, PD decreased cathepsin B levels, and DLB negatively correlated with cathepsin Z levels. However, no reverse causal relationship was found between AD and cathepsins. Conclusion While higher cathepsin H levels were associated with AD and DLB risk, the bidirectional association between PD and cathepsin B. By studying how cathepsin influences the development and advancement of AD, PD, and DLB, novel methods for diagnosis and treatment might be investigated.