Proteome-wide genetic study identified therapeutic targets for early-onset and late-onset Alzheimer's disease.

Backgrounds: Given the distinct pathogenic mechanisms of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD), identifying disease-specific therapeutic targets for each subtype is particularly critical. Methods: We performed proteome-wide Mendelian randomization (MR), colocalization analysis, summary-data-based MR, and Heterogeneity in Dependent Instruments (HEIDI) tests to identify the causal roles of candidate proteins in EOAD and LOAD. Further analyses included protein-protein interaction network analysis, GO/KEGG enrichment analyses, and single-cell RNA sequencing annotation. Druggability evaluation of the target proteins, Phenome-wide association study was conducted to systematically evaluate the potential adverse effects associated with druggable proteins. High-throughput molecular docking and molecular dynamics simulations were conducted to target the top therapeutic targets. Results: Genetically predicted levels of three proteins (APOE, NECTIN2, and PVR) were associated with EOAD risk, nine proteins (APOE, NECTIN2, PVR, EPHB4, SEMA3F, RNASET2, BTN1A1, PSAPL1, and GRN) were associated with LOAD risk, three proteins (APOE, NECTIN2, and PVR) were colocalized with EOAD, and six proteins (APOE, NECTIN2, PVR, SEMA3F, BTN1A1, and EPHB4) were colocalized with LOAD. Three of the proteins (APOE, NECTIN2, and PVR) serve as common targets for both EOAD and LOAD. EPHB4 and BTN1A1 were prioritized for LOAD with the most convincing evidence. The small molecule cucurbit[8]uril exhibits excellent binding affinity with both EPHB4 and BTN1A1 target proteins for the treatment of Alzheimer's disease. Conclusions: This study pinpointed APOE, NECTIN2, and PVR as shared therapeutic targets for EOAD and LOAD, and EPHB4 and BTN1A1 singled out as a priority target for LOAD.