Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy

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.

Hyperbaric oxygen therapy for healthy aging: From mechanisms to therapeutics

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Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

“…Over the past decade, hypercholesterolemia, characterized by high blood levels of cholesterol, and obesity have been considered risk factors for the development of neurodegenerative diseases [ 160 ]. One of the mechanisms proposed to explain this correlation seems to be that high levels of cholesterol and free fatty acids result in incorrect regulation of lipid metabolism, which alters the permeability of BBB inducing neuroinflammation and cognitive deficits [ 161 ].…”

Neurovascular Dysfunction in Diverse Communities With Health Disparities—Contributions to Dementia and Alzheimer’s Disease

“…Notably, the correlation of atherosclerosis, cardiovascular disease, and APOE4 was reported ( Bennet et al, 2007 ; Granér et al, 2008 ; Duong et al, 2021 ). APOE4 expression was highly correlated to neurovascular impairment, stroke, and AD ( Montagne et al, 2020b ; Pendlebury et al, 2020 ).…”