Aging Brain · 2026
The hypertension-NVU-cognition Axis: Mechanisms and interventions
By Tao Z
Midlife hypertension is a major modifiable risk factor for Alzheimer's disease, but the specific molecular pathways through which it contributes to cognitive decline—pathways that are partially independent of, and interact with, amyloid-β pathology—are not fully elucidated. This review synthesizes and elaborates the “Hypertension-NVU-Cognition” axis, building on the established cerebrovascular biology, neurovascular unit, cerebral small vessel disease (CSVD), and vascular cognitive impairment (VCID) literature, within which this axis is positioned as an integrative, complementary framework rather than a wholly novel or independent pathway. Sustained hypertension damages the neurovascular unit (NVU) through hemodynamic stress, blood-brain barrier (BBB) disruption (via tight junction and pericyte loss), and neuroinflammation (pro-inflammatory microglial activation and reactive astrogliosis). This NVU dysfunction directly impairs cognition via glutamate excitotoxicity, cholinergic axonal ischemia, and reduced Aβ clearance. Critically, midlife blood pressure trajectories are stronger predictors of late-life cognition than late-life levels. NVU injury frequently coexists with amyloid pathology, yet emerging evidence indicates it also contributes to cognitive decline in individuals with low amyloid burden, highlighting its complementary and potentially synergistic role alongside classical AD mechanisms. This axis highlights candidate molecular targets and biomarkers that merit further investigation for early intervention. Promising biomarkers include plasma sPDGFRβ (pericyte injury) and DCE-MRI Ktrans (BBB leakage). Promising future research directions include standardizing NVU biomarkers and conducting targeted trials that combine intensive blood pressure control with investigational NVU-protective agents (e.g., GLP-1 receptor agonists) in at-risk midlife individuals; these approaches are not yet clinically actionable and require validation in adequately powered randomized controlled trials. Understanding this axis is crucial for developing effective preventive therapies against vascular cognitive impairment.