Brain Endothelial Glycocalyx as a Blood-Facing Translational Interface in Alzheimer’s Disease: Beyond “Leaky” Barriers Toward Repair-First Stratification

Chungang Zhang,1,* Deyu Fang,2,* Lin Zhang3 1College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, People’s Republic of China; 2College of Artificial Intelligence and Information Engineering, Liaoning University of Traditional Chinese Medicine, Shenyang, People’s Republic of China; 3College of Basic Medical Sciences, Liaoning University of Traditional Chinese Medicine, Shenyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chungang Zhang, College of Pharmacy, Liaoning University of Traditional Chinese Medicine, No. 77, Life One Road, DD Port, Dalian, 116600, People’s Republic of China, Email [email protected] Lin Zhang, College of Basic Medical Sciences, Liaoning University of Traditional Chinese Medicine, No. 79, Chongshan East Road, Shenyang, 110847, People’s Republic of China, Email [email protected]: Alzheimer’s disease (AD) pathogenesis is increasingly recognized as involving blood-brain barrier (BBB) and neurovascular unit (NVU) destabilization. The brain endothelial glycocalyx—a blood-facing glycan-rich interface—represents a critical but under-characterized determinant of BBB dysfunction in AD. In this review, we systematically reappraised glycocalyx abnormality mechanisms, distinguishing robust causal evidence from murine models from limited human observational data. We propose a four-dimensional interface-state framework (structural, glycosylation, transport, inflammatory) to stratify patients beyond binary “leaky versus intact” classifications. Glycocalyx deterioration in AD reflects compartmentalized remodeling (early mucin-domain depletion) rather than uniform shedding. A reversible therapeutic window exists in APOE4 carriers and mild cognitive impairment, but collapses with concurrent cerebral amyloid angiopathy (CAA) or amyloid-related imaging abnormalities (ARIA). Pathological glycocalyx disruption amplifies nonproductive vascular retention rather than parenchymal penetration. We advocate a hierarchical “repair-first, transport-engineering-second, exploitation-last” strategy. This repositions the glycocalyx as a decisive arbiter governing BBB-targeted interventions in AD, not merely a structural appendage.Keywords: Alzheimer’s disease, blood-brain barrier, endothelial glycocalyx, mucin-type O-glycosylation, therapeutic stratification