BackgroundAlzheimer's disease (AD) is a major neurodegenerative disorder with limited treatment options.ObjectiveThis study aimed to identify novel therapeutic targets for AD using proteome-wide Mendelian randomization (MR) and colocalization analyses.MethodsWe conducted a large-scale, proteome-wide MR analysis using data from two extensive genome-wide association studies (GWASs) of plasma proteins: the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE Health Study. We extracted genetic instruments for plasma proteins from these studies and utilized AD summary statistics from European Bioinformatics Institute GWAS Catalog. Colocalization analysis assessed whether identified associations were due to shared causal variants. Phenome-wide association studies and drug repurposing analyses were performed to assess potential side effects and identify existing drugs targeting the identified proteins.ResultsOur MR analysis identified significant associations between genetically predicted levels of 9 proteins in the deCODE dataset and 17 proteins in the UKB-PPP dataset with AD risk after Bonferroni correction. Four proteins (BCAM, CD55, CR1, and GRN) showed consistent associations across both datasets. Colocalization analysis provided strong evidence for shared causal variants between GRN, CR1, and AD. PheWAS revealed minimal potential side effects for CR1 but suggested possible pleiotropic effects for GRN. Drug repurposing analysis identified several FDA-approved drugs targeting CR1 and GRN with potential for AD treatment.ConclusionsThis study identifies GRN and CR1 as promising therapeutic targets for AD. These findings provide new directions for AD drug development, but further research and clinical trials are warranted to validate the therapeutic potential of these targets.