Genetic Evidence of Association Between Plasma Cathepsin L2 and Alzheimer’s Disease: A Mendelian Randomization Study
Weibo Tian, Yitong Hao, Siqi Qiu, Zhe Chen, Xuelian Wu, Yu YangBackground:
Recent studies have suggested cathepsins, lysosomal cysteine proteases, are associated with Alzheimer’s DISEASE (AD). This study conducted Mendelian Randomization (MR) analysis to systematically assess the causal effect of genetically predicted plasma cathepsins levels on AD and AD endophenotypes (cognition and brain structure).
Method:
Recent large-scale Genome-Wide Association Studies (GWAS) in Europe provided summary statistics on plasma cathepsins, AD, cognition, and brain structure. The primary statistical estimate was employed by Inverse Variance Weighting (IVW). Various sensitivity analysis was performed to draw robust results, including Cochran's Q test, MR-Egger intercept test, and MR PRESSO.
Results:
Genetically predicted plasma cathepsin levels were not significantly associated with AD risk. Higher genetically predicted cathepsin L2 levels were associated with better fluid intelligence (β = 0.081, 95% CI 0.029 to 0.133, P = 0.00230, adjusted P = 0.0207). The associations of cathepsin L2 with general cognitive function (β = 0.081, 95% CI 0.010 to 0.152, P = 0.0247, adjusted P = 0.2226) and white matter hyperintensity volume (WMH, β = -0.068, 95% CI -0.134 to -0.002, P = 0.0433, adjusted P = 0.3898) were considered exploratory. Cathepsin L2 was also associated with monocyte count after correction across the three evaluated immune-cell traits (nominal P = 0.0133, FDR-adjusted P = 0.0285); the estimated indirect effect through monocyte count was -0.0016.
Discussion:
These findings identify cathepsin L2 as the most consistently associated candidate with fluid intelligence and additional exploratory signals across cognitive, neuroimaging, and peripheral immune-cell phenotypes. The association with monocyte count raises a testable hypothesis regarding a peripheral immune-related pathway. Further studies using larger protein GWAS datasets, stronger genetic instruments, and independent populations are required to validate these findings.
Conclusion:
Genetically predicted plasma cathepsin L2 levels were associated with fluid intelligence after multiple comparisons. Although the immune-cell analyses raised the possibility of a monocyte-related peripheral pathway, the present findings did not establish a statistically supported mediating effect or a direct protective effect of cathepsin L2 against AD.