The Glymphatic System: Importance of Sleep for Clearance of Brain Protein Waste

Neurons with amyloid plaques (right side) compared to healthy neurons (left). Amyloid plaques accumulate outside neurons. Amyloid plaques are characteristic features of Alzheimer’s disease. They lead to a degeneration of the affected neurons, that are destroyed through the activity of microglia cells.
Degradation of the glymphatic system over time due to age and sleep disturbance may be associated with neurodegenerative dementias.

The glymphatic system, which is most active during sleep, clears the brain of protein waste products, and degradation of this system over time may be linked to increased risk of dementia, according to a review published in Science.

The glymphatic system, a highly organized cerebrospinal fluid transport system, exports excess interstitial fluid and proteins from the brain via the glymphatic pathway. This pathway is a distinct system of fluid transport that relies on perivascular spaces made by astrocytes’ vascular endfeet.

Aging typically leads to some form of protein aggregation in the brain, which is associated with an increased risk of dementia. Additionally, the quality of sleep decreases with increasing age, ultimately resulting in a decline in brain waste clearance. Study researchers suggested that disrupted sleep in older individuals may therefore significantly decrease the clearance of brain fluid and protein waste export, potentially accelerating the course of neurodegeneration.

In animal models, glymphatic fluid transport and amyloid-β export is facilitated by the polarized expression of AQP4 in the vascular endfeet of astrocytes. And in humans, genetic variation in AQP4 impacts sleep and amyloid-β burden. In other studies, a common single-nucleotide polymorphism of AQP4 was associated with changes in slow-wave activity during non-REM sleep, changes which were reflected in daytime sleepiness and altered reaction times during prolonged wakefulness.

According to the review authors, available research on the glymphatic system emphasizes the importance of a good night’s sleep on potentially supporting proper protein waste clearance from the brain. They added that “the development of small-molecule agonists of glymphatic efflux might present opportunities to slow disease progression in the aggregation disorders,” but more research is ultimately needed.


Nedergaard M, Goldman SA. Glymphatic failure as a final common pathway to dementia. Science. 2020;370(6512):50-56. doi:10.1126/science.abb8739