Abstract
A BSTRACT This review synthesizes emerging evidence underlying apparent blood–brain barrier paradoxes and proposes an expanded conceptual framework incorporating vascular and lymphatic components in aging, inflammation, and neurodegeneration. A structured literature review of peer-reviewed studies and authoritative reviews published between 2016 and 2026, with selected foundational studies, was conducted across major biomedical databases. Accumulating evidence indicates that blood–brain barrier function is governed by regulated transport processes, endothelial signaling, and pericyte-dependent regulation. Human imaging and cerebrospinal fluid biomarker studies reveal early, region-specific barrier dysfunction associated with cognitive impairment and APOE4-related risk. However, several paradoxes, including protein accumulation, immune trafficking, and microplastic retention, cannot be fully explained by blood–brain barrier dynamics alone. Emerging evidence of lymphatic vessels within brain parenchyma suggests a complementary clearance system, indicating that these paradoxes may reflect combined dysregulation of vascular entry and lymphatic drainage. The blood–brain barrier should therefore be reconceptualized not as an isolated barrier but as part of an integrated neurovascular–lymphatic interface, with important implications for biomarkers, diagnosis, and mechanism-based therapies in neurodegenerative disease.