Association of Cathepsin Proteins with Alzheimer's Disease Risk: An Integrated Observational and Genetic Analysis.

Alzheimer's disease (AD) involves complex lysosomal proteolytic dysfunction, but the specific roles of cathepsin family proteins remain unclear. This study aimed to systematically evaluate the association of cathepsins with AD risk and to explore underlying mechanistic pathways integrating neuroimaging, cognitive, and genetic evidence. We analyzed data from 52,988 UK Biobank participants. Plasma levels of 11 cathepsins were measured via Olink proteomics. Associations with AD diagnosis, cognitive performance, and brain structural measures were assessed using multivariable regression. Mediation analysis tested pathways through cognition and brain structure. Bidirectional two-sample Mendelian randomization (MR) was used to assess potential directional associations, and colocalization analysis was performed to identify shared genetic signals. Among the cathepsins analyzed, CTSL was the most coherent signal across observational analyses, showing associations with AD diagnosis, poorer cognitive performance, and reduced volume in AD-vulnerable regions including the hippocampus. Exploratory mediation analyses identified indirect associational patterns involving cognition and brain structure. Bidirectional MR provided genetic evidence for a positive directional association of genetically predicted CTSL with AD diagnosis (β = 1.2666 on the log-odds scale, p < 0.001) and for a reverse association of AD liability with higher CTSL levels (β = 0.5556, p < 0.001). Colocalization initially suggested a shared signal in the APOE/ZNF285 region, but this signal was not independent of APOE after sensitivity analysis. CTSL emerged as a candidate plasma molecule associated with AD across observational and genetic analyses. These findings support further longitudinal and experimental evaluation of CTSL, while the mechanistic interpretation remains preliminary.