Vascular cognitive impairment and dementia (VCID) is increasingly recognized as one of the leading causes of cognitive decline in aging populations. VCID is driven by the interplay of endothelial dysfunction, chronic inflammation, oxidative stress, and metabolic dysregulation. Aging exacerbates cerebrovascular damage by impairing endothelial function, compromising the blood-brain barrier (BBB), and promoting neuroinflammation, all of which contribute to the progression of small vessel disease (SVD) and white matter hyperintensities (WMHs), which are hallmarks of VCID. Epidemiological evidence suggests that aging is associated with modifications in circulating low-density lipoprotein (LDL) and high-density lipoproteins (HDL), particularly oxidation, which further accelerates neurovascular pathology. Oxidized LDL (oxLDL) disrupts endothelial homeostasis, enhances leukocyte adhesion, and triggers chronic inflammatory signaling through microglial and astrocytic activation. Additionally, oxLDL-mediated oxidative stress exacerbates mitochondrial dysfunction and epigenetic alterations in cerebrovascular cells, reinforcing a cycle of vascular injury and neurodegeneration. These mechanisms contribute to neurovascular uncoupling, cerebral hypoperfusion, and cognitive decline in aging individuals. This review examines the pathophysiological role of oxLDL in VCID, with a focus on its impact on endothelial integrity, BBB function, neuroinflammation, and lipid-mediated neurodegenerative processes. Furthermore, we discuss emerging therapeutic strategies targeting LDL oxidation, inflammation, and endothelial dysfunction as potential interventions to mitigate the burden of VCID in aging populations. • OxLDL links dyslipidemia to cerebrovascular aging in brains. • LOX-1/redox signaling drives endothelial dysfunction and BBB leak. • Neuroinflammation, mitochondrial stress, and hypoperfusion worsen small-vessel disease and cognition. • Therapeutic opportunities: limit oxidation, block receptors, restore endothelial resilience.
Ihuoma et al. (Sun,) studied this question.