“Morphological, Functional, and Molecular Progression of Blood-Brain Barrier Dysfunction in Alzheimer’s Disease”

Abstract

Blood-brain barrier (BBB) dysfunction is increasingly recognized as an early pathological event in sporadic Alzheimer’s disease (AD), which represents over 95% of cases. Vascular risk factors and cerebral insulin resistance are considered potential contributors to its initiation. This review synthesizes evidence available through March 2026 on the temporal progression of morphological, functional, and molecular BBB alterations in AD patients and experimental models. This review emphasizes the proposed role of BBB disruption in perpetuating neurodegeneration through feedback loops involving pericyte damage, hypoxia, perivascular inflammation, and dysregulation of amyloid-β transport systems. By integrating data from neuroimaging, fluid biomarkers, and post-mortem studies, available evidence suggests that BBB alterations can be detected from preclinical stages, most consistently in the hippocampus, and may exhibit sex-specific differences. The review compares findings from familial transgenic models with the more limited characterization available in sporadic AD models (notably the intracerebroventricular streptozotocin model), and highlights key knowledge gaps regarding temporal dynamics. This synthesis supports further exploration of strategies to preserve BBB integrity. An integrated vascular approach may usefully complement current amyloid- and tau-centered therapies, particularly in sporadic AD.