Cleaning the Brain: Inside the Glymphatic System

For decades, neuroscience textbooks taught that the brain lacked a dedicated waste-clearance system. Unlike the rest of the body, which relies on lymphatic vessels to remove metabolic byproducts, the brain appeared to have no equivalent. That assumption has changed in the last decade with the discovery of the glymphatic system - a specialised, brain-wide pathway that clears waste, redistributes nutrients, and may even play a critical role in brain health.  

What Is the Glymphatic System?

The glymphatic system is a glia-dependent fluid transport network that facilitates the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) within the brain. Its name reflects this hybrid role, combining glial cells and the lymphatic system.

At its core are astrocytes, star-shaped glial cells whose endfeet densely wrap around cerebral blood vessels. These endfeet express high levels of aquaporin-4 (AQP4) water channels, which enable CSF to flow from periarterial spaces into the brain parenchyma (Mader & Brimberg, 2019). As CSF enters, it mixes with ISF, collecting metabolic waste - such as amyloid-β, tau, and lactate - before exiting along perivenous routes and ultimately draining into meningeal and cervical lymphatic vessels. 

In short, the glymphatic system acts as the brain’s sanitation and recycling service, maintaining neural homeostasis.

Sleep: The Glymphatic System’s Prime Time

One of the most striking findings in glymphatic research is its close relationship with sleep. Glymphatic clearance is dramatically enhanced during non-REM (non-rapid eye movement) sleep, when noradrenergic tone decreases (hypoarousal), astrocytes change volume, and the interstitial space expands by up to ~60% (Xie et al., 2013). 

Figure 1: How sleep boosts brain clearance. (A) 3D reconstruction showing how cerebrospinal fluid (CSF) tracers spread through a mouse brain while it was sleeping, compared with the same mouse when awake. (B) Time-course of CSF flow 100 μm below the cortical surface, showing that tracer influx is much higher during sleep. Data from 6 mice.

This expansion reduces resistance to fluid flow, allowing waste products to be cleared far more efficiently than during wakefulness. Even short-term sleep deprivation reduces glymphatic function, offering a compelling biological explanation for why chronic poor sleep is linked to cognitive decline and brain disease. If you’re curious to learn more about what your brain gets up to while you sleep, you can read our blog The Night’s Work: How Sleep Impacts Your Brain Function.

Sex Differences in Glymphatic Function

Emerging evidence suggests that glymphatic function differs between sexes, shaped by hormonal, vascular, and inflammatory factors (Han et al., 2023).

Oestrogen and progesterone appear to influence astrocyte physiology and AQP4 expression. Experimental studies suggest that oestrogen can enhance glymphatic efficiency by supporting healthy blood-vessel pulsatility, reducing neuroinflammation, and preserving AQP4 localisation at astrocytic endfeet. These effects may help to explain why premenopausal women show relative protection against some neurodegenerative processes, despite having a higher lifetime risk of conditions such as Alzheimer’s disease.

After menopause, glymphatic efficiency declines more sharply in females, coinciding with hormonal withdrawal, increased vascular stiffness, and changes in sleep patterns (Han et al., 2023). This timing aligns with the rise in Alzheimer’s incidence among older women, although whether glymphatic dysfunction is a cause or a consequence remains an open question.

Glymphatic Dysfunction in Neurological Disease

Impaired glymphatic clearance has been implicated across a range of neurological conditions. In Alzheimer’s disease, reduced clearance of amyloid-β and tau contributes to their accumulation, shifting the focus from overproduction to failed removal (Mader & Brimberg, 2019). Disrupted glymphatic flow is also seen after traumatic brain injury, where astrocyte reactivity, swelling, and blood-brain barrier damage can impair clearance long after the initial insult, potentially increasing the risk of chronic neurodegeneration. Similarly, stroke and cerebral small vessel disease interfere with the vascular dynamics that drive glymphatic exchange, contributing to white matter damage and cognitive decline (Ang et al., 2024). In Parkinson’s disease, reduced glymphatic clearance of α-synuclein may accelerate protein aggregation and disease progression (Lv et al., 2026).

Migraine and Glymphatic Dysfunction

While the glymphatic system is often discussed in the context of neurodegeneration, there is growing evidence that it may also play a role in migraine.

Recent studies using established mouse models show that glymphatic function is disrupted during migraine-like attacks (Huang et al., 2023). In these animals, CSF flow through the brain was reduced, along with decreased expression of astrocytic AQP4 channels. When glymphatic activity is further impaired, migraine symptoms worsen, with increased pain sensitivity, heightened neuronal activation, and greater neuroinflammation.

Put simply, when the brain’s ‘clean-up’ system isn’t working efficiently, migraine pathology may be amplified rather than resolved. It also offers a potential explanation for why sleep disruption - a well-known migraine trigger - can make attacks more frequent or more severe. If sleep is when the glymphatic system does most of its work, missing out on those hours may leave inflammatory molecules and neuropeptides hanging around longer than they should.

Although much of this work has been performed in animal models, it opens up intriguing questions about migraine in humans. Could impaired waste clearance be one of the factors that tips the brain into a migraine attack? And, could improving sleep or supporting glymphatic function help reduce migraine burden?

Open Questions and Future Directions

As imaging techniques improve and human studies expand, the glymphatic system is increasingly viewed, not as a curiosity, but as a central pillar of brain health. Despite rapid advances, major questions remain:

• Can glymphatic function be safely enhanced therapeutically?

• How do posture, breathing, and physical activity influence clearance?

• Is glymphatic dysfunction a cause or consequence of disease?

Conclusion

The discovery of the glymphatic system has reshaped how we think about the brain - not as a static organ sealed off from waste removal, but as a dynamic structure deeply dependent on sleep, vascular health and glial biology. Understanding how this system fails may unlock new strategies for preventing and treating some of the most prevalent neurological diseases of our time.

References

• Ang, P. S., Zhang, D. M., Azizi, S. A., Norton de Matos, S. A., & Brorson, J. R. (2024). The glymphatic system and cerebral small vessel disease. Journal of Stroke and Cerebrovascular Diseases, 33(3). https://doi.org/10.1016/j.jstrokecerebrovasdis.2024.107557

• Han, F., Liu, X., Yang, Y., & Liu, X. (2023). Sex-specific age-related changes in glymphatic function assessed by resting-state functional magnetic resonance imaging. BioRiv. https://doi.org/10.1101/2023.04.02.535258

• Huang, W., Zhang, Y., Zhou, Y., Zong, J., Qiu, T., Hu, L., Pan, S., & Xiao, Z. (2023). Glymphatic Dysfunction in Migraine Mice Model. Neuroscience, 528, 64–74. https://doi.org/10.1016/j.neuroscience.2023.07.027

• Lv, Y., Ding, X. S., Gao, L., Han, Z., Feng, C. X., Li, Y. N., Wang, Y. F., Yang, Q., Simon, D. K., Wang, X. lian, Qu, Y., & Wang, B. (2026). Glymphatic dysfunction in Parkinson’s disease: Aging-associated impairments, imaging biomarkers, and therapeutic strategies. In Ageing Research Reviews(Vol. 114). Elsevier Ireland Ltd. https://doi.org/10.1016/j.arr.2025.102995

• Mader, S., & Brimberg, L. (2019). Aquaporin-4 water channel in the brain and its implication for health and disease. In Cells (Vol. 8, Issue 2). MDPI. https://doi.org/10.3390/cells8020090

• Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., Takano, T., Deane, R., & Nedergaard, M. (2013). Sleep Drives Metabolite Clearance from the Adult Brain. Science, 342(6156), 373–377. https://www.science.org

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This article was written by Neave Smith and edited by Rebecca Pope, with graphics produced by Suzana Sultan. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.