Chronic Cerebral Hypoperfusion Induced Vascular Dementia: Pathophysiology, Glial Mechanisms, and Therapeutic Perspectives

Vascular contributions to cognitive impairment and dementia (VCID) have emerged as critical determinants of age-related cognitive decline, yet they remain insufficiently recognized in both clinical practice and research. This comprehensive review synthesizes current understanding of the pathophysiological mechanisms linking chronic cerebral hypoperfusion (CCH) to vascular dementia (VaD) and related cognitive disorders. We examine the epidemiology, classification, and clinical heterogeneity of vascular cognitive impairment, emphasizing the convergence of cerebrovascular pathology on common pathogenic cascades including neurovascular unit dysfunction, white matter degeneration, neuroinflammation, and blood–brain barrier disruption. Particular attention is directed toward the selective vulnerability of specific brain regions to chronic hypoperfusion, the molecular mechanisms driving persistent neuroinflammation, and the role of peripheral immune cell infiltration in disease progression. We critically evaluate experimental models of CCH and discuss emerging therapeutic strategies including ischemic preconditioning and remote ischemic conditioning. Finally, we highlight the importance of sex differences in disease susceptibility, progression, and therapeutic response, emphasizing the need for sex-specific approaches in future research and clinical management.