Mindy Nguyen

Background: Alzheimer’s Disease (AD) is the most common form of dementia and is characterized by slow and gradual loss of declarative episodic memory.¹ Aging leads to higher susceptibility of neurodegeneration and reduced vasculature function. Diminished efflux of waste products from meningeal lymphatic vessels (mLVs) can lead to the buildup of proteins and exacerbate conditions such as AD or PD, where the build up of certain proteins leads to cognitive and motor effects.² The meningeal lymphatic system is essential in the removal of cellular debris and metabolic products and mediate the immune inflammatory responses.³ The functionally related glymphatic system is also a CSF clearance system that is facilitated by AQP4, with higher activity while sleeping.⁴ Modulation of either the mLV or glymphatic systems to enhance efflux of waste and protein aggregates is therefore a novel but promising therapeutic option for AD and other intracranial pathology.

Objective(s): In this narrative review, we examined the potential mediators of the meningeal lymphatic and glymphatic systems such as sleep deprivation, infrared light, and chemotherapy as possible routes of enhancing CSF flow.

Search Methods: ​​An online search in the PubMed database was conducted from 2017 to 2025 using the following keywords: “meningeal lymphatics”, “glymphatic”, “neurodegeneration”, and “Alzheimer’s Disease”.

Results: Studies comparing meningeal lymphatic flow of tracers indicate that aging is associated with impaired mLV function.⁵ CSF-derived apoE distributes into the brain via glymphatic pathways and is responsible for carrying cholesterol.⁶ Sleep deprivation and aging significantly reduces apoE transport, impairing Aβ clearance and increasing AD risk.⁶ In infrared light-treated mice, there was notably higher OVA-A647 tracer draining to the cervical lymph nodes than in untreated mice, demonstrating improved meningeal lymphatic drainage with light modulation.⁷ Mechanistically, infrared light enhances mitochondrial respiration in meningeal lymphatic endothelial cells, facilitating improved repair mechanisms of lymphatic junctions.⁷ Further studies performed on traumatic brain injury (TBI) models showed that mislocalization of AQP4, an important glymphatic channel, exacerbates acute inflammation and cerebral edema.⁸ Polarity reversal using siRNA to inhibit mislocalization accelerated the reduction of swelling and edema, suggesting a broader therapeutic application for managing glymphatic dysfunction and neuroinflammation.⁸ Inflammation-induced lymphangiogenesis, as observed in rodent models with chronically implanted electrodes, also enhanced glymphatic inflow and efflux.⁹ These results indicate that low levels of inflammatory stimuli may stimulate reactive lymphatic sprouting, leading to improved CSF clearance.⁹

Conclusion: This review explores the impact of aging, sleep deprivation, and injury on glymphatic and meningeal lymphatic dysfunction that may worsen cognition. It also introduces new interventions such as light therapy and AQP4 modulation. These findings support emerging therapeutic strategies for improving waste clearance in neurodegenerative diseases like Alzheimer’s. Future research can investigate long-term effects of lymphatic enhancement in human subjects. Despite gaps in research, there is potential to reshape clinical approaches in neurodegeneration and trauma.

Works Cited:

1. Erkkinen MG, Kim MO, Geschwind MD. Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2018;10(4):a033118. Published 2018 Apr 2. doi:10.1101/cshperspect.a033118
2. Oliver G, Kipnis J, Randolph GJ, Harvey NL. The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease. Cell. 2020;182(2):270-296. doi:10.1016/j.cell.2020.06.039
3. Wang M, Yan C, Li X, et al. Non-invasive modulation of meningeal lymphatics ameliorates aging and Alzheimer’s disease-associated pathology and cognition in mice. Nat Commun. 2024;15(1):1453. Published 2024 Feb 16. doi:10.1038/s41467-024-45656-7
4. Achariyar TM, Li B, Peng W, et al. Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation [published correction appears in Mol Neurodegener. 2017 Jan 12;12(1):3. doi: 10.1186/s13024-016-0147-7.]. Mol Neurodegener. 2016;11(1):74. Published 2016 Dec 8. doi:10.1186/s13024-016-0138-8
5. Zhou Y, Cai J, Zhang W, et al. Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human. Ann Neurol. 2020;87(3):357-369. doi:10.1002/ana.25670
6. Achariyar TM, Li B, Peng W, et al. Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation [published correction appears in Mol Neurodegener. 2017 Jan 12;12(1):3. doi: 10.1186/s13024-016-0147-7.]. Mol Neurodegener. 2016;11(1):74. Published 2016 Dec 8. doi:10.1186/s13024-016-0138-8
7. Wang M, Yan C, Li X, et al. Non-invasive modulation of meningeal lymphatics ameliorates aging and Alzheimer’s disease-associated pathology and cognition in mice. Nat Commun. 2024;15(1):1453. Published 2024 Feb 16. doi:10.1038/s41467-024-45656-7
8. Lu H, Zhan Y, Ai L, Chen H, Chen J. AQP4-siRNA alleviates traumatic brain Edema by altering post-traumatic AQP4 polarity reversal in TBI rats. J Clin Neurosci. 2020;81:113-119. doi:10.1016/j.jocn.2020.09.015
9. Hauglund NL, Kusk P, Kornum BR, Nedergaard M. Meningeal Lymphangiogenesis and Enhanced Glymphatic Activity in Mice with Chronically Implanted EEG Electrodes. J Neurosci. 2020;40(11):2371-2380. doi:10.1523/JNEUROSCI.2223-19.2020