Vascular cognitive impairment and dementia: current understanding and future directions
TL;DR
By emphasizing the interplay between systemic vascular health and brain resilience, this Review highlights opportunities to target endothelial dysfunction, neuroinflammation, and metabolic stress as promising strategies for prevention and therapy of vascular dementia.
Abstract
Dementia affects over 55 million individuals worldwide, and its prevalence is projected to triple by 2050. Vascular dementia (VaD) is the second most common cause of cognitive impairment after Alzheimer’s disease (AD), accounting for roughly 20% of all cases. VaD represents a heterogeneous yet mechanistically convergent group of disorders in which vascular injury, blood–brain barrier (BBB) disruption, and neuroinflammation synergistically drive progressive cognitive decline. It arises from diverse etiologies including small-vessel and large-artery disease, chronic cerebral hypoperfusion, and hereditary arteriopathies such as CADASIL, but converges on shared downstream pathways that impair cerebral perfusion, white-matter integrity, and neuronal connectivity. As the global burden of cardiovascular disease rises, vascular contributions to dementia are expected to increase disproportionately, particularly in aging populations. Importantly, epidemiologic evidence consistently links VaD risk to modifiable cardiovascular and metabolic disorders, most notably hypertension, diabetes, and obesity, underscoring its largely preventable nature. Advances in single-cell and spatial transcriptomics, vascularized human brain organoids, and experimental models have revealed how endothelial senescence, oxidative stress, impaired glymphatic clearance, and immune dysregulation disrupt the neurovascular unit. Furthermore, mounting evidence supports bidirectional interactions between vascular injury and amyloid-β and tau pathology, suggesting shared mechanisms between VaD and AD. This Review synthesizes current mechanistic, epidemiologic, and translational insights into vascular contributions to cognitive decline. By emphasizing the interplay between systemic vascular health and brain resilience, we highlight opportunities to target endothelial dysfunction, neuroinflammation, and metabolic stress as promising strategies for prevention and therapy of vascular dementia.