Update information. Vascular depression (VaD) is considered a depressive syndrome occurring associated with cerebrovascular disease and vascular risk factors. The study aims to analyze the proteomic signature and identify promising biomarkers with diagnostic significance for vascular depression (VaD). Deep profiling of serum proteome in vascular depression (VaD) patients(n=35) and age/sex matched controls(n=36) were analyzed by bioinformatics and machine learning, our results uncovered several potential biomolecular markers (eg, FTO) and biological pathways (eg, synaptic vesicle cycle) related to VaD. Monitoring protease expression differences can help in the diagnosis and prognosis of VaD. We believe this manuscript will provide new issues for readers working on the field of depression among the elderly.