Biomarkers of the blood–brain barrier and the neurovascular unit and their relationship with cognitive decline and cognitive frailty

Aging is accompanied by an increasing prevalence of frailty and age-related cognitive decline (CD). Cognitive frailty (CF), characterized by physical frailty and cognitive impairment, has been associated with oxidative stress, neuroinflammation, mitochondrial dysfunction, and cardiovascular impairment. However, its biological foundations remain only partially understood. This review synthesizes evidence on biomarkers associated with the blood-brain barrier (BBB) and neurovascular unit (NVU) in CD and CF. These biomarkers are associated with endothelial injury, pericyte damage, BBB permeability, tight junction disruption, glial activation, and extracellular vesicles (EVs). They are assessed by analyzing cerebrospinal fluid (CSF), blood, neuroimaging (including DCE-MRI), and histology. The most frequently evaluated markers were CSF sPDGFRβ, the CSF/serum albumin ratio (QAlb), DCE-MRI permeability, and the adhesion molecules ICAM-1 and VCAM-1. Key convergent findings suggest that BBB breakdown (particularly pericyte injury, as indicated by elevated CSF sPDGFRβ) can precede or occur independently of classical amyloid-β and tau pathology, predict CD in APOE4 carriers over up to 4.5 years, and be associated with disrupted default mode network connectivity. Elevated QAlb demonstrated dose-response prognostic value for clinical deterioration, while DCE-MRI permeability was associated with poorer episodic memory and predicted white-matter injury, which mediated cognitive impairment. Endothelial activation markers were elevated early and predicted progression, whereas vWF exhibited a stage-dependent, potentially biphasic association. Overall, BBB/NVU biomarkers support vascular and neuroinflammatory mechanisms as early, partially Alzheimer's disease-independent contributors to CD and CF, with significant modification by APOE4 and metabolic comorbidities, and with distinct signatures across Alzheimer's disease and vascular cognitive impairment.