Causal relationship between cathepsin and neurodegenerative diseases: a Mendelian randomization study

Abstract Background Observational studies indicate a strong association between cathepsins and neurodegenerative disorders, although the underlying causal relationship remains unclear. Methods This research utilized Mendelian Randomization (MR) with genetic markers associated with 11 different types of cathepsins (including cathepsins D, L1, B, E, F, G, H, O, S, L2, and Z) as instrumental variables and analyzed public Genome-Wide Association Studies (GWASs) summary statistics derived primarily from individuals of 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 genetically predicted associations between cathepsins and 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). Reverse MR research was done to improve forward MR analysis. Additionally, Bayesian weighted MR (BWMR) was used to further validate the robustness of the results. Results After correcting for the false discovery rate (FDR), genetically predicted cathepsin H levels were positively associated with AD risk, whereas cathepsin B levels were inversely associated with PD risk. Effect estimates in MVMR and BWMR analyses with cathepsins as variables remained constant. No significant associations were observed for cathepsin D or cathepsin L1 on any neurodegenerative phenotype. Reverse MR analysis revealed a negative connection between PD and cathepsin B levels and a negative correlation between DLB and cathepsin Z levels. No evidence of reverse associations was observed between AD and cathepsins. Conclusions This study provides genetic evidence supporting potential associations between cathepsin H and AD, as well as a bidirectional relationship between cathepsin B and PD. These findings highlight the potential utility of specific cathepsins as biomarkers in neurodegenerative diseases. Further studies are warranted to explore underlying mechanisms.