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. 2025 Jan;15(1):e70207.
doi: 10.1002/brb3.70207.

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

Yanhong Jiang  1 , Wenhui Fan  1 , Yaxin Li  1 , Hua Xue  1
Affiliations

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

Yanhong Jiang et al. Brain Behav. 2025 Jan.

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.

Keywords: Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; cathepsins; mendelian randomization.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Flow chart of the study design. AD, Alzheimer's disease; ALS, Amyotrophic lateral sclerosis; IVW, inverse variance weighted; LOO, leave‐one‐out; PD, Parkinson's disease; SNP, single nucleotide polymorphism; WM, weighted median.
FIGURE 2
FIGURE 2
Forest plots of cathepsins on Alzheimer's disease. CI, confidence interval; IVW, inverse variance weighting; OR, odds ratio; WM, weighted median.
FIGURE 3
FIGURE 3
Forest plots of cathepsins on Parkinson's disease. CI, confidence interval; IVW, inverse variance weighting; OR, odds ratio; WM, weighted median;
FIGURE 4
FIGURE 4
Forest plots of cathepsins on amyotrophic lateral sclerosis. CI, confidence interval; IVW, inverse variance weighting; OR, odds ratio; WM, weighted median.
See this image and copyright information in PMC

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