The Glymphatic System
Dennis Lenz
A breathing mask, two alternating gas mixtures, and a 35-second interval form the surprisingly simple experimental setup employed by researchers from New Mexico to investigate if the brain’s cleansing system can be activated while awake. The CO2 inhalation simulates the slow vascular movements that typically occur only during deep sleep. Effects were measured using brain scans and blood samples before and after half an hour of exposure to these conditions.
(Photo: © Forschung und Wissen)
The brain has its own drainage system, predominantly active during deep sleep, tasked with transporting proteins linked to Alzheimer’s disease. A research team from New Mexico has tested whether this process can also be triggered while awake. Twelve volunteers inhaled a mixture of air with 0.05% and 5% carbon dioxide for 30 minutes through a mask. The accompanying brain scans and blood samples revealed patterns that the researchers admit require further explanation.
Albuquerque (U.S.A.). For a long time, the brain was considered the only organ without a lymphatic system. It is only in the past decade that research has confirmed the presence of a unique waste disposal pathway, known as the glymphatic system. This system functions effectively to transport metabolic waste products along blood vessels from nervous tissue by compressing cerebrospinal fluid through the narrow spaces between cells. This flow is driven by vasomotion, the rhythmic dilation and constriction of arteries about every 30 seconds. This rhythm acts like a slow pump and is most active during Non-REM sleep, where slow brain waves and vascular movements synchronize. This correlation highlights deep sleep’s significance for brain health and sheds light on the long-discussed risk of chronic sleep deprivation leading to neurodegenerative diseases.
This cleansing is not merely a side note in sleep research. Substances such as Beta-Amyloid and Tau protein, which accumulate as plaques and fibrils in Alzheimer’s disease, are among those eliminated during this process. According to estimates from the German Alzheimer Society, around 1.84 million individuals live with dementia in Germany, most of whom have Alzheimer’s. By 2050, this number could rise to 2.3 to 2.7 million. Consequently, approaches to enhance the clearance of these proteins without altering metabolism are of great interest. Research has primarily focused on improving sleep and physical activity, but whether this nightly brain cleansing can be deliberately triggered in awake individuals has long remained uncertain.
Alternating CO2 Bursts Every 35 Seconds
Led by neuropsychologist Sephira Ryman from the Mind Research Network and the University of New Mexico, a team presented data on an unusual approach at the Alzheimer’s Association International Conference in London. Instead of extending sleep or using medications, the researchers utilized a gas that the body constantly produces. Twelve participants wore a mask for 30 minutes, alternating between two mixtures every 35 seconds. One contained approximately 0.05% carbon dioxide, akin to the concentration in ambient air, while the other contained 5%, a hundredfold increase. Controlled hypercapnia visibly dilates brain vessels, as the body responds to rising CO2 levels in the blood by expanding arteries. This constant switching created an artificial rhythm of dilation and constriction, mirroring the slow pace of vasomotion during deep sleep. Eight out of twelve participants had normal Tau levels in their blood, while four showed elevated levels, three of them also exhibiting mild cognitive impairment.
What Brain Scans and Blood Samples Revealed
During the session, magnetic resonance imaging was conducted. The scans demonstrated that the intermittent CO2 exposure in the awake brain triggered cerebrospinal fluid movement patterns usually observed predominantly during Non-REM sleep. Previously, the team had tested this principle on Parkinson’s patients and described it in a study on cerebrospinal fluid flow under intermittent hypercapnia, where three sessions of ten minutes each increased the inflow of cerebrospinal fluid. Crucially, blood values are significant for this approach. After half an hour, all twelve participants showed an increase in Beta-Amyloid concentration in their blood. Initially seeming unfavorable, researchers believe this indicates that the protein was expelled from the brain into the circulatory system. Additionally, increased clearance of Tau proteins was noted in the three participants with cognitive impairment, likely because they had a higher amount present in their tissue from the outset.
Short-lived Effects
While the findings are remarkable, their limitations are evident. Additional blood tests revealed that Amyloid and Tau values returned to baseline levels one hour after the treatment. Thus, the CO2 inhalation induces a temporary window of enhanced cleansing but not a permanent state. Whether this translates into measurable benefits for memory remains unanswered. The sample size of twelve participants is also very small, making it difficult to derive assumptions for safety, despite no side effects being reported. Planned clinical studies will explore how often such a session would be necessary and whether repeated applications are safe. Concurrently, research is developing methods to detect early cognitive decline, such as smartphone tests for detecting early Alzheimer’s changes that could allow for closer monitoring of progress.
Extending Beyond Alzheimer’s Disease
The appeal of this method for the researchers lies in its non-targeted approach; accelerating clearance impacts molecules like Alpha-Synuclein, involved in Parkinson’s, as well as pro-inflammatory messengers. Neuroscientist Jeff Iliff, who contextualizes this work, views it as a potential application area that extends well beyond Alzheimer’s disease. However, it remains unclear whether a heightened cleansing process can genuinely slow cognitive decline, as deposits are considered markers but not the sole cause of the disease. The complexity of this interplay is reflected in studies examining whether partial memory regeneration in Alzheimer’s is even achievable. Should this approach prove both safe and effective, researchers envision a scenario where patients could one day use a small device at home to stimulate their brain’s cleansing process.
npj Parkinson’s Disease, The influence of intermittent hypercapnia on cerebrospinal fluid flow and clearance in Parkinson’s disease and healthy older adults; doi:10.1038/s41531-025-01179-6
