Figure 2.

Working model of cholesterol, APOE4, and stromal activation in (A) VCID and (B) AD. (A) Risk factors (hypercholesterolemia, hypertension, smoking, APOE4) trigger atherosclerosis via cholesterol-rich plaques with local/systemic inflammation and stromal dysfunction (glia, macrophages, smooth muscle, endothelium, pericytes). Lipid-induced inflammation impairs lipid turnover and exacerbates plaque formation. This leads to ischemia (arrowheads) and dementia as detected by fluid-attenuated inversion recovery MRI. (B) Amyloid and tau pathology, with risk factors and APOE4, trigger neuronal injury. Subsequent proteinopathy-associated glial activation and lipid deposits (from glial proliferation and myelin debris) hinder amyloid/tau aggregate clearance and promote accumulation. This leads to aggregate spread and neurodegeneration (arrowheads) as seen on T2-weighted MRI.