Journal Article Review Ahead of print
PubMed: 42264186 DOI: 10.1016/j.arr.2026.103202
Impaired Glymphatic Clearance as a Mechanistic Link Between Brain Aging and Neurodegenerative Disease Pathogenesis.
Ageing Res Rev
Authors: Abida Khan, Abdullah R Alzahrani, Zia Ur Rehman, Neelam Singla, Faiyaz Shakeel, Yahia Hassan Ali, Intisar Kamil Saeed, Mohd Imran
Affiliations
- Center for Health Research, Northern Border University, Arar 73213, Saudi Arabia; Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha, Saudi Arabia.
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Al-Abidiyah, P.O. Box 13578, Makkah 21955, Saudi Arabia.
- Health Research Centre, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia; Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia.
- Department of Pharmacy, Suresh Gyan Vihar University, Jaipur, Rajasthan, India.
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Jadara Research Center, Jadara University, Irbid 21110, Jordan.
- Department of Biological Sciences, College of Science, Northern Border University, Arar 73251, Saudi Arabia.
- Center for Health Research, Northern Border University, Arar 73213, Saudi Arabia; Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha, Saudi Arabia.
Abstract
The perivascular glymphatic system promotes cerebrospinal fluid-interstitial fluid (CSF-ISF) interaction and macromolecular waste clearance and is an important determinant of brain homeostasis, the performance of which deteriorates with age. Astrocyte biology, vascular integrity, and age-associated cerebrovascular dynamic alterations interfere with the polarization of aquaporin-4 (AQP4) water channels on astrocytic endfeet, decreasing the clearance of aggregation-prone proteins, such as amyloid-β, tau, and α-synuclein. Experimental research indicates that aging is associated with a decrease in cerebrospinal fluid influx and solute clearance efficiency, and human neuroimaging research indicates progressive age-related dysfunction of glymphatic transport, which is associated with pathological protein accumulation and cognitive impairment. Glymphatic dysfunction is mechanistically associated with clearance failure and disease progression in Alzheimer 's and Parkinson's diseases and is also observed in other age-related diseases, such as cerebral small vessel disease, traumatic brain injury, and neuroinflammatory disease. Emerging evidence suggests that glymphatic efficiency can be restored by intervening in some of the underlying aging processes, including sleep regulation, cardiovascular health, astrocyte-vascular coupling, and pharmacological manipulation of AQP4 polarisation. This review places glymphatic dysfunction as a fundamental, potentially alterable outcome of brain aging with the implication of preventing neurodegenerative diseases and supporting healthy cognitive aging.
MeSH
Aquaporins, Aging, Brain, Research, Neurodegenerative Diseases