Neurovascular unit dysfunction in vascular cognitive impairment: Mechanisms, biomarkers, and translational strategies

Vascular cognitive impairment and dementia (VCID) encompasses a heterogeneous spectrum of cognitive disorders driven by cerebrovascular pathology and represents a major contributor to late-life cognitive decline. VCID is highly prevalent and frequently coexists with Alzheimer's disease pathology. Despite this, it remains poorly defined in clinical practice and lacks approved disease-modifying therapies. Therapeutic development has been hindered by biological heterogeneity, challenges in patient stratification, and a historical emphasis on neurodegenerative targets that inadequately address vascular mechanisms. Increasing evidence implicates dysfunction of the neurovascular unit-including small vessel disease, chronic hypoperfusion, blood-brain barrier disruption, and neuroinflammation-as a central driver of vascular-mediated cognitive impairment and a unifying therapeutic target across diverse VCID phenotypes. In this review, we synthesize current understanding of VCID pathobiology with a focus on neurovascular unit dysfunction and emerging mechanism-based strategies aimed at restoring vascular and neurovascular homeostasis. We further examine translational considerations for targeting neurovascular signaling pathways, including endothelial stabilization, modulation of vascular inflammation, and preservation of blood-brain barrier integrity. As an illustrative example, we discuss preclinical evidence supporting Mas receptor agonism, including the glycosylated angiotensin-(1-7) analogue PNA5, as a potential approach to address vascular-mediated cognitive impairment. Finally, we explore implications for biomarker selection, patient enrichment, and early clinical trial design. Together, this framework highlights neurovascular dysfunction as a tractable therapeutic target in VCID and underscores the need for mechanism-driven approaches to address a substantial unmet clinical need.