Human apolipoprotein E (apoE) has 3 isoforms: apoE2, apoE3, and apoE4. APOE4 is a major genetic risk factor for Alzheimer disease and is associated with dementia in Down syndrome and poor neurological outcome after traumatic brain injury, cerebral hemorrhage, and other neuropathological disorders. While apoE4 can induce neuropathology by participating in various cellular and molecular pathways, herein I review data supporting the hypothesis that apoE4 has direct toxic effects on the cerebrovascular system that in turn can lead to secondary neuronal dysfunction and degeneration as well as accumulation of neurotoxins in brain such as β-amyloid (Aβ) in Alzheimer disease. I review Aβ-independent cerebrovascular effects of apoE, particularly activation of a proinflammatory cyclophilin A-mediated pathway in brain vascular pericytes by apoE4 that has recently been shown to lead to a loss of cerebrovascular integrity and blood-brain barrier breakdown causing neuronal injury. I also review Aβ-dependent cerebrovascular effects of apoE such as faulty Aβ clearance from brain to circulation by apoE4. Finally, I discuss isoform-specific interactions of apoE with low-density lipoprotein receptor-related protein 1 on brain vascular cells (ie, endothelial cells, pericytes), which play an important role in Aβ-independent and Aβ-dependent effects of apoE on cerebral vasculature.