An early-onset AD mice model expressing human APOE4 (E4-FAD) also showed BBB breakdown, reduced cerebral blood flow, neuronal loss and behavioral deficits, compared to E3-FAD mice, and the removal of astrocytic APOE4 in APOE4-KI mice ameliorated leaky BBB and abnormal level of MMP9 transcript (Montagne et al., 2021; Jackson et al., 2022). This evidence concerns the gene APOE and Alzheimer disease.