Alzheimer's disease (AD) is a common cause of dementia in elderly people. The ε4 allele of the apolipoproteinE (apoE) gene is a known risk factor for AD. ApoE gene alleles may shift the onset of AD through apoE protein isoforms changing the probability of amyloid-β (Aβ) accumulation. Additionally, chronic cerebral hypoperfusion have been a risk factor for cognitive decline in patients with AD. However, the association with ε4 allele and chronic cerebral hypoperfusion in the molecular pathogenesis of AD is still unknown. The purpose of this study was to examine the association with ε4 allele and chronic cerebral hypoperfusion using apoE4 and apoE3 knock in mice. The experimental animals were divided into 4 groups as follows, apoE3 knock in mice (E3 cont) group, apoE3 with common carotid artery (CCA) occlusion (E3 occl) group, apoE4 knock in mice (E4 cont) group, apoE4 with CCA occlusion (E4 occl) group. Chronic cerebral hypoperfusion underwent by permanent occlusion of left CCA at the age of 12 weeks. All mice were sacrificed at the age of 60 weeks. After the sacrifice, brains and plasmas were removed and served for experimentation. The E4 mice were significantly decreased daily physical activity, and increased the area of Aβ-positive cell in the hippocampus compared with E3 mice. The number of the neuron in hippocampus of E4 occl group was significantly reduced compared with that of other three groups. The E4 occl group were significantly increased the expression of Aβ-positive cell and neurofibrillary tangles in hippocampus compared to the other three groups. The level of Aβ42 in plasma of apoE4 occl group was significantly increased compared with that of E3 mice. These results suggested that chronic cerebral hypoperfusion in apoE4 knock in mice decreased the number of neuronal cell in the hippocampus, and increased the Alzheimer's disease-related factors such as Aβ-positive cell and neurofibrillary tangles. The onset of Alzheimer's disease in ApoE4 carriers may be related with chronic cerebral hypoperfusion.