Abstract
Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may 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, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.
Highlights
Vascular contributions to cognitive impairment and dementia (VCID) are defined by cognitive impairment secondary to acute and/or chronic cerebral ischemia and encompass the classical term, vascular dementia (Gorelick et al, 2011; Iadecola et al, 2019)
VCID is strongly associated with cerebral atherosclerosis, the chronic dysfunction of lipid homeostasis, and local inflammation caused by the accumulation of cholesterol, cholesteryl esters (CEs), other lipids, and activated stromal cells, including lipid-laden foamy macrophages, endothelial, and smooth muscle cells of vessel walls (Glass and Witztum, 2001; Hansson et al, 2006)
VCID is often associated with hypercholesterolemia, wherein elevated serum cholesterol promotes a cascade of cerebrovascular cholesterol deposition, inflammation, ischemia, neuronal injury, and cognitive impairment (Solomon et al, 2009; Appleton et al, 2017)
Summary
Vascular contributions to cognitive impairment and dementia (VCID) are defined by cognitive impairment secondary to acute and/or chronic cerebral ischemia and encompass the classical term, vascular dementia (Gorelick et al, 2011; Iadecola et al, 2019). VCID is strongly associated with cerebral atherosclerosis, the chronic dysfunction of lipid homeostasis, and local inflammation caused by the accumulation of cholesterol, cholesteryl esters (CEs), other lipids, and activated stromal cells, including lipid-laden foamy macrophages, endothelial, and smooth muscle cells of vessel walls (Glass and Witztum, 2001; Hansson et al, 2006). VCID is often associated with hypercholesterolemia, wherein elevated serum cholesterol promotes a cascade of cerebrovascular cholesterol deposition, inflammation, ischemia, neuronal injury, and cognitive impairment (Solomon et al, 2009; Appleton et al, 2017).
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