Mendelian randomization analysis implicates several cathepsin isoforms—most notably cathepsin F—as inversely associated with Parkinson's disease risk, while other isoforms show links to Alzheimer's and epilepsy, but many associations rely on few SNP instruments and European-only data.

Highlights lysosomal cathepsins (especially cathepsin F) as plausible causal contributors and potential biomarker/therapeutic targets for PD, providing a genetically informed rationale for follow-up functional studies and target validation despite requiring replication.

INTRODUCTION: Recent studies indicate that cathepsins play an important role in neurodegenerative diseases. However, further exploration is required to determine the association between each isoform of cathepsin and disease. This study aimed to evaluate the potential causal effects of individual cathepsin isoforms on Alzheimer's Disease (AD), Parkinson's Disease (PD), and epilepsy using Mendelian Randomization (MR). METHODS: We used genome-wide association data from the IEU OpenGWAS database. Twosample MR analyses were performed, with Inverse Variance Weighting (IVW) serving as the primary method. Sensitivity analyses, including Cochran's Q test, MR-Egger regression, MRPRESSO, Steiger directionality test, and leave-one-out analysis, were conducted to validate the robustness of the findings. RESULTS: In this study, cathepsins A, B, and F were found to be negatively associated with PD, and a sensitivity analysis was performed to assess the causal association between cathepsin F and PD. The results showed no heterogeneity or pleiotropy. However, the associations for cathepsin A and cathepsin B were each supported by only one SNP, and thus should be interpreted with caution. We also found that cathepsin X is causally related to AD, but this estimate was based on only 2 SNPs, and sensitivity analyses could not be conducted; therefore, the result should be considered exploratory. In addition, we found a positive causal association between Pro-cathepsin H levels, Cathepsin L1 levels, and epilepsy. The sensitivity analyses showed that the results were reliable for these exposures with multiple instrumental variables. Given the limited number of SNPs and the exclusive use of European-ancestry data, these findings should be interpreted cautiously. DISCUSSION: The results showed that there was no heterogeneity or pleiotropy. We also found that cathepsin X is causally related to Alzheimer's disease, but due to the small number of instrumental variables, no sensitivity analysis was performed. In addition, we found a positive causal association between Pro-cathepsin H levels and Cathepsin L1 levels and epilepsy. The sensitivity analyses showed that the results were reliable. CONCLUSION: This study found that different cathepsin isoforms could participate in different neurodegenerative diseases, and have differences in their function, providing preliminary evidence for their potential roles in disease mechanisms.