In this study, we developed 5xFAD AD mice carrying human APOE3 or APOE4, along with their non‐AD controls, to investigate the impact of APOE4 compared to APOE3 on AD progression during the presymptomatic stage, focusing on cognitive function, Aβ deposition, microglial activation, and BBB permeability. Here, APOE is linked to Alzheimer disease.