Abstract Body: Background: White Matter Hyperintensities (WMH) are a radiographic manifestation of cerebral small vessel disease (CSVD), representing myelin and axonal loss. Currently, no drugs specifically target or reduce the burden of WMH. Integrating genomic and proteomic data may identify proteins as potential targets to slow WMH progression. Particularly promising are proteins that serve as pathway-level hubs through which polygenic effects converge.
Methods: We analyzed data from 53,014 participants enrolled in the UK Biobank. The analytical pipeline involved (Figure 1): 1) linear regression analyses between a polygenic risk score of WMH (from 27 independent variants) and normalized levels of 2,923 proteins ascertained at baseline, adjusting for age, sex, and genetic principal components; 2) evaluation of proteins selected in step 1 for association with WMH volume, ascertained through dedicated research MRIs; 3) mediation analyses to confirm that proteins with significant and directionally concordant associations with both the polygenic score and WMH are indeed mediators of the polygenic score-WMH relationship; 4) Mendelian Randomization using cis-protein quantitative trait loci as instruments to evaluate the causality between selected proteins and WMH and other clinical manifestation of CSVD. Each step was adjusted for multiple testing using Bonferroni correction.
Results: Our analyses identified two proteins (Cathepsin B and ECHDC3) that met all the criteria to mediate the polygenic effect of CSVD on WMH. However, only one of these, Cathepsin B, was confirmed by Mendelian Randomization (Beta: -0.092, SE: 0.003, P<0.001). Mendelian Randomization also confirmed the association between Cathepsin B and the risk of intracerebral hemorrhage, small vessel stroke, perivascular spaces volumes, and alterations in white matter microstructure (Figure 2).
Conclusions: Our combined genetic and proteomic approach successfully identified Cathepsin B as a protein linked to WMH and other CSVD phenotypes. Cathepsin B, a lysosomal protease, is well-known for its involvement in programmed cell death, including hypoxia/ischemia-induced neuronal death, a key pathophysiological process leading to WMH (Figure 3). Compounds targeting Cathepsin B have shown promising results in reducing neuronal death and neurotoxicity in Alzheimer’s disease models, where WMH often precedes disease onset. This finding provides a basis for repurposing Cathepsin B-targeting compounds to stabilize WMH burden.