Genetic Insights Into the Role of Cathepsins in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis: Evidence From Mendelian Randomization Study

Abstract Background Previous studies have confirmed the significant role of cathepsins in the development of neurodegenerative diseases. We aimed to determine whether genetically predicted 10 cathepsins may have a causal effect on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Methods We conducted a two‐sample bidirectional Mendelian randomization (MR) study using publicly available data from genome‐wide association study (GWAS) to assess the causal associations between 10 cathepsins and three neurodegenerative diseases, including AD, PD, and ALS. We employed the following methods, including inverse variance weighting (IVW), MR‐Egger, and weighted median (WM). The results were further validated using sensitivity analysis. Results The forward MR analysis results indicate that elevated cathepsin H levels increase the risk of AD ( p = 0.005, odds ratio [OR] = 1.040, 95% confidence interval [CI] = 1.011–1.069), elevated cathepsin B levels decrease the risk of PD ( p < 0.001, OR = 0.890, 95% CI = 0.831–0.954), and no significant association was found between cathepsin levels and ALS. Reverse MR analysis suggests that there is no causal association between 10 cathepsins and three neurodegenerative diseases. Conclusion Our study provides new genetic insights into the role of cathepsin H in AD and cathepsin B in PD. However, our findings need to be further validated in a wider population, and future research should explore the potential mechanisms of cathepsins in these diseases in order to provide a basis for the development of new therapeutic strategies.