Despite effective clearance of parenchymal amyloid-β (Aβ) in patients with Alzheimer’s disease, Aβ immunotherapy exacerbates the vascular Aβ (VAβ)-associated pathology in the brain. We have previously shown that BCG immunization facilitates protective monocyte recruitment to the brain of APP/PS1 mice. Here, we confirmed that the 4Aβ1-15 vaccine exacerbates VAβ deposits in this model, which coincides with a decrease in the number of cerebrovascular endothelial cells and pericytes, infiltration of neutrophils into the brain, and induction of cerebral microhemorrhage. Moreover, combined 4Aβ1-15/BCG treatment abrogates the development of the VAβ-associated pathology. In addition, BCG treatment is required for the upregulation of interleukin-10 in the brain. Notably, BCG treatment selectively enhances Aβ phagocytosis by recruited macrophages. Furthermore, combined 4Aβ1-15/BCG treatment is more effective than 4Aβ1-15 monotherapy in synaptic preservation and the enhancement of the learning efficiency. Overall, our study suggests that the combination of Aβ-targeted therapy with an immunomodulatory strategy may improve the efficacy of Aβ vaccine in Alzheimer’s disease.