Cerebrovascular disease (CVD) encompasses a broad spectrum of pathologies affecting cerebral blood vessels, so the balance between tissue circulatory supply and cerebral metabolic demands is impaired. Ischemic stroke stands out as the most frequent cause of death and disability among these diseases. Still, a growing understanding of other CVDs reveals their important impact on the population’s length and quality of life. Apolipoprotein E (apoE) is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It was previously described as a lipid transport protein and primary ligand for low-density lipoprotein receptors, which play a role in cholesterol metabolism and cerebrovascular disease. ApoE is associated with increased cognitive decline, and dementia may occur after ischemic and hemorrhagic stroke or traumatic brain injury. It is also a significant genetic risk factor for Alzheimer’s disease (AD) and is associated with dementia in Down’s syndrome and other neuropathological disorders such as multiple sclerosis, frontotemporal dementia, and Parkinson’s disease. ApoE4 promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. It may also contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, vascular contributions to cognitive impairment, and neurodegeneration. The relevance of studies involving apoE in neurobiology comes from the great convergence of mechanisms and biological processes involving this protein. Studies with apoE have highlighted prophylactic and therapeutic possibilities for CVD, bringing potential changes in the progression of these conditions for an aging population.