Dr Varga is a neurologist and sleep specialist at the Mount Sinai Integrative Sleep Center in New York. He attended the 2025 SLEEP meeting in Seattle, Washington, and he’s here to update us on the glymphatic system and why it’s important.
Welcome, Dr Andrew Varga.
Andrew W. Varga, MD, PhD: Thank you so much for having me.
Glymphatic System and Sleep
Wilner: Dr Varga, I’m really interested to learn about the glymphatic system. The first time I saw it, frankly, I thought it was a typo. It’s not the lymphatic system. It’s the glymphatic system, which is something they didn’t have when I was in medical school. Tell us about the glymphatic system.
Varga: Sure. The glymphatic system is a system that allows communication between the interstitial fluid, the fluid that kind of surrounds individual cells in the brain, and the spinal fluid itself, which is surrounding the entirety of the brain, circulating around, and helping to do things like clear metabolites.
Wilner: How is it that we didn’t know about this before? It’s only been, what, 10 years or so that anybody’s known about the glymphatic system? I mean, it’s been there for thousands of years, right?
Varga: I don’t fully know the answer to that. I think some of it has to do with techniques available to measure that exchange. I think that the finding that really put the glymphatic system on the map, so to speak, was a 2013 paper that described that glymphatic function may be one of sleep’s functions.
This paper described that, when mammals sleep, all the cells in the brain actually shrink down in size. What that leads to, ultimately, is an expansion of this interstitial space, that now more easily allows clearance of different metabolites right out of the brain parenchyma itself and into the spinal fluid where it can be cleared.
As part of that paper, one of the things that the experimenters did was to introduce exogenous beta amyloid that was radiolabeled and look at how quickly that radiolabeled beta amyloid egress out of the brain parenchyma during situations of wakefulness, sleep, or anesthesia.
The gist was that, during sleep or anesthesia, the beta amyloid was exiting the brain much more quickly. Suddenly this became a potential mechanism by which sleep or disruptions to sleep may be contributing toward worsening of underlying Alzheimer’s pathology.
Sleep and Amyloid and Tau Production
Wilner: That’s pretty exciting. I mean, we’ve known for a long time that, clinically, sleep deprivation is bad, right? Human performance deteriorates, memory deteriorates, people become delirious, and they can have seizures. If you keep people awake long enough, bad things happen, and the brain doesn’t function well. I think it’s never really been clear why that is. Maybe the glymphatic performance of cleaning the waste products out of the brain is part of that. Is that what you think?
Varga: I think that is certainly a potentially contributing factor. There are a couple of other ideas that I think are not mutually exclusive. Another idea is that neural activity drives the production of things like amyloid and tau. Although the brain is not universally silent or quiet during sleep, there certainly are some areas of the brain during sleep which are firing much less, and you can buy into this idea that the firing rate makes more amyloid and tau be produced.
During consolidated, nice sleep, those neurons are firing less and making less amyloid and tau, but with disrupted sleep, from a variety of disorders, suddenly now those neurons, which are ordinarily quiet, fire more and make more amyloid and tau. That’s another mechanistic hypothesis. As I was saying earlier, again, the glymphatic system is another one, and I don’t think these are mutually exclusive.
Wilner: We have a natural model of people with chronic sleep disruption, and you probably see them every day — people with sleep apnea. Is there any evidence that people with sleep apnea are at increased risk to develop Alzheimer’s or to develop it earlier than the general population?
Varga: There’s, I would say, increasing evidence that those links exist. For full disclosure, my lab is a big mover and shaker in this area. Much of what I’m about to cite is my own research.
I would say one of the early findings that we had, which was really eye-opening, was that we did some data mining from the Alzheimer’s Disease Neuroimaging Initiative, or ADNI, cohort. These were people who were followed longitudinally, starting from a time at which they’re cognitively normal. Many remain cognitively normal, but subsets of people go on to develop either mild cognitive impairment or Alzheimer’s disease.
That study didn’t do super careful sleep apnea phenotyping or screening, but they did ask people subjectively whether they carried a diagnosis of sleep apnea or not. If people said yes, then they were asked a follow up question, which is, “Do you use a CPAP machine to treat your sleep apnea?” They mostly said no.
Although the level of apnea data was, again, fairly subjectively or rudimentary, one of the nice parts of ADNI was that these people were followed very carefully with serial neurological exams and cognitive exams. In those people who did convert to either mild cognitive impairment or Alzheimer’s disease, a fairly precise age at which that conversion happened could be known.
When we did some of the analysis, we found that those people who reported no sleep apnea had an average age of conversion to mild cognitive impairment that was around 83 years of age. In those people who self-reported, “yes, I have sleep apnea, but I don’t use any CPAP to treat it,” their average age of conversion to mild cognitive impairment was 11 years earlier, at 72 years of age.
The thing that was particularly fascinating was that it was a relatively small number of people, but those people who said, “yes, I do have a diagnosis of sleep apnea,” but also, “yes, I used a CPAP machine to treat it regularly,” had an average age of conversion of around 82 years of age. This was much closer to those people who reported not having any sleep apnea at all and obviously much later than those people who had untreated sleep apnea.
This suggests that sleep apnea may not only be a risk factor for acceleration of cognitive decline, but it may be a modifiable risk factor if you use a CPAP machine to treat it.
How to Keep the Glymphatic System Healthy
Wilner: I’ve got a couple burning questions. First, I don’t want to develop Alzheimer’s disease, so what can I do to keep my glymphatic system healthy?
Varga: Make sleep a priority. Make sure you’re getting enough duration and enough quality. The duration is something that I think does evolve with age. Most adults need somewhere between 6 and 9 hours of sleep. As you get to be a little bit older, there’s some thought your sleep needs may go down in some older adults.
The National Sleep Foundation, for example, has a yellow caution sign at 5-6 hours of sleep, saying that it’s not clearly red, it’s not clearly bad, but we’re not putting it in the green either. In any case, duration’s important and the continuity’s important. Continuity and timing. There’s some thought that consistent bedtimes and consistent awake times were also very useful.
Certainly, if there’s any concern that there might be a sleep disorder going on, it should warrant a visit with a sleep doctor. Insomnia and sleep apnea are probably the two most common sleep disorders. Insomnia, I would argue, is a little bit more obvious to the person who is experiencing it whereas sleep apnea sometimes is not. Particularly if a person lives alone, they may not be aware that they’re snoring, that they’re choking and gasping and having many interruptions to sleep.
They would sometimes rely on daytime function as a clue. If people are getting sufficient duration of sleep, say 7 or 8 hours, but they’re very sleepy during the day and they’re napping all the time, that should trigger some warning signs. They should question why this is happening and maybe talk to either a primary care doctor or a sleep doctor about why that might be happening and get tested.
Wilner: Now as important as it is to get good sleep, is there a risk if you’re using pharmaceuticals to sleep better, which is pretty common, right? Are those facilitating the work of the glymphatic system by helping you sleep, or could those be actually interfering with the glymphatic system because it’s not a “natural” sleep? What do you think about that?
Varga: That, I think, is an area of a bit of controversy for sure. There is a paper that came out in the British Medical Journal several years ago that made a pretty big splash because it suggested that the use of really a wide variety of sleep aids that mostly included benzodiazepines, but some other non-benzodiazepines like Ambien and some other medicines, seem to increase risk for subsequent cognitive decline. That paper was a little bit problematic in the sense that they didn’t carefully control for the intrinsic risk of the reason why people are taking those things.
I think that a diagnosis of insomnia, for example, is something that increases risk for Alzheimer’s disease. People with insomnia are often taking the medicine. There are risks to having disrupted sleep, and I think some of these medicines can help with that and actually reduce risk.
I was part of it a team led by Bhanu Kolla at the Mayo Clinic in Minnesota that actually looked at a large cohort of people longitudinally that had insomnia and looked at to what extent having a diagnosis of insomnia predicted longitudinal gains in amyloid over time, and it did.
Then there was a sub-analysis looking at, well, what about people being on these different medicines, and it looked like that didn’t impact things very strongly. It was a signal that using the medicine to treat insomnia is not adding extra risk, at least for the accumulation of amyloid.
I will add that, recently, there was a paper that did suggest that potentially zolpidem specifically, or Ambien, could be negatively impacting glymphatic clearance, even though it is something that augments sleep. This is, again, adding a little bit of controversy to this. I would just say, I think, the jury’s still out about zolpidem, in particular.
Wilner: It’s clear that medical students have one more thing to learn about these days. It sounds like we’re going to learn much more in the next few years about the role of the glymphatic system and how it can help keep us healthy. Is there anything else you’d like to add before we wrap up?
Varga: It’s a really exciting field and I think that much of the work in the glymphatic system to date has largely been in animal models, mostly in rodents. I think there’s a big need to really bring this into people more. There are definitely many groups that are starting to think about how to do this more.
I think what’s been a bit of a challenge is that many of the tools that we have to measure glymphatic function in people rely on brain imaging measures that are at best a proxy for glymphatic clearance, and in most cases, are not direct measurements of glymphatic clearance.
Much of that is changing. I think because people have recognized that some of these imaging techniques do have limitations, there’s been a big push to develop novel tools and ways to glymphatic culture in people that go beyond certain imaging sequences.
Wilner: Dr Andrew Varga, thanks for bringing us up to date on the glymphatic system.
Varga: Thank you.
Wilner: I’m Dr Andrew Wilner, reporting for Medscape.
Andrew Wilner is an associate professor of neurology at the University of Tennessee Health Science Center, Memphis, and a seasoned neurologist and epilepsy expert who has mastered the less conventional locum career path. He is the author of four books, including Bullets and Brains, and hosts the podcast The Art of Medicine with Dr. Andrew Wilner.
