Dysfunction of the Blood-Brain Barrier and Glymphatic System in Alzheimer’s Disease: An Integrative Review
Daniel Nuciatelli P. de Mello1, Irineu Gregnanin Pedron2*
1DDS, Specialist in Oral Implantology, São Paulo, Brazil; Master's Student in Clinical Neuroscience, University of Roehampton, London, UK.
2Professor, Department of Periodontology and Integrated Clinic, School of Dentistry, Centro Universitário Braz Cubas, Mogi das Cruzes, Brazil.
*Corresponding Author: Irineu Gregnanin Pedron, Professor, Department of Periodontology and Integrated Clinic, School of Dentistry, Universidade Braz Cubas, Mogi das Cruzes, Brazil.
DOI: https://doi.org/10.58624/SVOANE.2026.07.009
Received: March 05, 2026
Published: March 25, 2026
Citation: de Mello DNP, Pedron IG. Dysfunction of the Blood-Brain Barrier and Glymphatic System in Alzheimer’s Disease: An Integrative Review. SVOA Neurology 2026, 7:2, 51-58. doi. 10.58624/SVOANE.2026.07.009
Abstract
Alzheimer’s disease (AD) represents the most prevalent cause of dementia globally, characterised neuropathologically by amyloid-β plaques and tau neurofibrillary tangles. While these hallmarks remain central to diagnosis, the modest clinical efficacy of amyloid-targeting therapies necessitates exploration of complementary pathogenic mechanisms. This review synthesises contemporary evidence implicating the coupled dysfunction of the blood-brain barrier (BBB) and glymphatic system as critical, early contributors to Alzheimer’s pathophysiology. The BBB, a selective vascular interface, and the glymphatic system, a brain-wide clearance network dependent on astrocytic aquaporin-4 (AQP4), are fundamental to cerebral homeostasis. Their impairment facilitates neuroinflammation, reduces clearance of neurotoxic proteins, and exacerbates neuronal injury. We integrate mechanistic insights from animal models with human neuroimaging studies, demonstrating that BBB permeability and glymphatic inefficiency often precede significant atrophy and predict cognitive decline. Key modulators including ageing, APOE4 genotype, chronic sleep disruption, and systemic inflammation are examined. Notably, emerging links between peripheral conditions like periodontitis and BBB integrity are explored. The review also critically evaluates nascent therapeutic strategies aimed at restoring vascular integrity and clearance function, alongside essential ethical and social considerations. We emphasise that biological sex differences and sociocultural constructs of race and ethnicity significantly influence disease risk, research participation, and healthcare access, demanding inclusive scientific practices. Ultimately, viewing Alzheimer’s disease through the lens of brain homeostasis failure offers a transformative framework for developing early biomarkers, preventive interventions, and novel treatments that move beyond exclusively amyloid-centric models.
Keywords: Alzheimer’s Disease, Blood-Brain Barrier, Glymphatic System, Neuroinflammation, Sleep Quality, Aquaporin-4, Periodontitis, Neuroimaging.
