Neurovascular Dysfunction and Glymphatic Impairment: An Unexplored Therapeutic Frontier in Neurodegeneration

Neurodegenerative diseases pose major clinical challenges partly due to the underappreciation of the brain's vascular and clearance systems. Evidence suggests that neurovascular dysfunction and glymphatic impairment are early contributors to disease onset, preceding established markers such as protein aggregation. This review synthesizes recent advances in understanding how disruption of the neurovascular unit (NVU) and glymphatic pathways contributes to neurodegeneration. We analyzed published literature documenting the temporal relationship between vascular dysfunction, glymphatic clearance impairment, and subsequent neurodegenerative pathology, with a focus on identifying therapeutic targets within this axis. Current research demonstrates that blood-brain barrier BBB breakdown, pericyte dysfunction, and compromised cerebral perfusion precede protein aggregation in multiple neurodegenerative disorders. Glymphatic dysfunction, characterized by aquaporin-4 (AQP4) depolarization and abnormalities in meningeal lymphatic vessels, impairs the clearance of neurotoxic metabolites. Novel therapeutic opportunities include the preservation of pericyte function, restoration of AQP4 polarity, enhancement of meningeal lymphatic drainage via vascular endothelial growth factor-C (VEGF-C)/vascular endothelial growth factor receptor-3 VEGFR-3 signaling, and targeted modulation of microRNA and complement pathways that regulate neuroinflammation. By targeting the earliest vascular and glymphatic disruptions, emerging therapeutic strategies may halt or delay disease progression before irreversible neuronal loss occurs. This neurovascular-glymphatic approach represents an unexplored frontier that complements traditional protein-centric therapeutic paradigms, offering new possibilities for early intervention in neurodegenerative disorders.