The Glymphatic System and Sleep Cycle’s Role in Dementia Risk

Karl Doghramjji, MD

The importance of sleep—and its potential effects on cognitive function—for those at risk of developing Alzheimer disease and dementia cannot be understated. At the Third International Congress on the Future of Neurology, September 17-18, 2021, the opening session offered an in-depth look at the current knowledge of the role of sleep in neurodegenerative disease and pointed to the plethora of new research in this area.

As has been known for some time, sleep is an essential part of the biologic function of human beings and all mammals. Without it, there are myriad systemic consequences, including increased pain sensitivity, depression, aggravated hypoxemia, cardiovascular complications, metabolic abnormalities, and negative immune system response, among others. Although these points are well-known, the underlying mechanisms of sleep and the biologic drivers of its operation are less understood.

A main focus of this Medical Crossfire® session was on the recently discovered glymphatic system—a macroscopic waste clearance system which utilizes astroglial cell-mediated perivascular tunnels to stimulate the efficient elimination of soluble proteins and metabolites from the central nervous system (CNS). Besides these duties, the glymphatic system also appears to enable brain-wide distribution of several compounds, such as glucose, lipids, amino acids, growth factors, and neuromodulators.^1-3 Notably, though, the system functions mainly during sleep, aiding the ongoing elimination of neurotoxic wastes such as amyloid ß— insinuating a potential connection to neurodegenerative conditions following the interruption of such processes driven by a lack of sleep.^1,2

“One of the exciting data points to give us a sense as to what might be the mechanism was the discovery that ß-amyloid clearance from the brain is preferentially higher during sleep. These poisons that accumulate during wakefulness are preferentially excreted from the brain during sleep in animals,” Karl Doghramjji, MD, medical director, Jefferson Sleep Disorders Center; professor of psychiatry and human behavior and associate professor of neurology, Jefferson University, said in the session. “This discovery was fascinating in many ways because for many years, we’ve known that the brain has to get rid of these toxic compounds, and we know that there are certain mechanisms like local proteolytic degradation and phagocytosis, but those did not account for the majority of poisons that build up in the brain.”

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Stephen Silberstein, MD, director, Jefferson Headache Center, and the session’s moderator, pointed out the connections between the glymphatic system and sleep stages—specifically pointing to slow-wave sleep. Previously, slow-wave sleep has also been tied to the metabolic processes. The stage of sleep, he noted, drives 2 things: the opening of the glymphatic system, and the waves of spinal fluid flushing around the brain.

Silberstein noted that norepinephrine closes down the glymphatic system, marking an interesting connection with norepinephrine antagonists—often used with individuals who present with agitation or disorientation to the intensive care unit. “There are a lot of things that we do, but we haven’t quite put it all back together,” he explained.

Doghramji noted that the potential ramifications of disruptions to the sleep process are numerous, including the possibility that poor sleep may mediate the buildup of amyloid-ß and tau plaques in the brain, thus driving the development of diseases such as Alzheimer. Additionally, he pointed out that a commonly, getting proper sleep can be a challenge for individuals as they age, presenting a potential additional mechanism of disease progression.

Carlos H. Schenck, MD, senior staff psychiatrist, Hennepin Healthcare and Minnesota Regional Sleep Disorders Center, and assistant professor, University of Minnesota, chimed in to note that recent research has identified an association with average sleep duration in middle and older age with the incidence of dementia, ultimately finding that there was a higher risk of dementia associated with sleep of less than 6 hours at ages 50 and 60 years compared with sleep of 7 hours or more.⁴ Additional data have implied that the alteration of peripheral metabolic signals induced by sleep restriction is responsible for cognitive deficit and AD development.⁵

“Persistent short sleep duration at age 50, 60, and 70 [years] compared to persistent normal sleep duration was also associated with a 30% increased dementia risk, independent of socioeconomic, behavioral, cardiometabolic, and mental health factors,” Schenck said. “We need to send a message to all physicians—particularly primary care physicians—to really assess the sleep duration by and large for most nights for their patients and emphasize that they need to get as much as 7 hours of sleep or more to really help them later on in life.”

Doghramji posed what he called a “chicken or the egg” question, wondering if the sleep deprivation being observed in these individuals is being caused by the underlying disease processes, or if the deprivation itself is causing the disease. Schenck noted that while the answers to that question remain unknown, his belief is that sleep deprivation is a driver of the disease.

Schenck said that ideally, an assessment of people who can shift from less than 6 hours of sleep to closer to 7 hours of sleep would be able to identify a reduction in their dementia risk. Doghramji added that some research has already suggested that experimental sleep reduction translates to a reduction in the glymphatic system flow, and that sleep reduction itself contributes to brain process dysfunction, pointing to that idea’s potential. “The associations are so potentially strong,” he said.

Right now, Doghramji noted that a major challenge in this area is the ability to measure sleep deprivation among the general public. Exactly what levels are considered dangerous and leads to catastrophic consequences are relatively unknown and being able to better test the glymphatic system’s operation in some way may help lead to the prevention of not only neurodegeneration, but occupational and lifestyle hazards such as car crashes.

Schenck noted that for neurologists who are treating patients with mild cognitive impairment and early Alzheimer disease, “these are the patients that really need to get 7 hours of sleep to really slow down—or at least, temporarily halt—the progression to greater cognitive impairment.”

“Increased sleep might be an important part of our therapeutics, in general, with patients. Just like we say you need a certain amount of nutrients in this area, or that you must have a certain amount of vitamins, sleep may become one of those critical areas where we might be able to say, ‘This much sleep is important for you because of the fact that it restores brain function, and with any less than that, you just can’t function,’” Doghramji explained.

REFERENCES
1. Jessen NA, Munk ASF, Lundgaard I, Nedergaard M. The Glymphatic System: A Beginner's Guide. Neurochem Res. 2015;40(12):2583-99. doi:10.1007/s11064-015-1581-6
2. Benveniste H, Liu X, Koundal S, Sanggaard S, Lee H, Wardlaw J. The Glymphatic System and Waste Clearance with Brain Aging: A Review. Gerontology. 2019;65:106-119. doi:10.1159/000490349
3. Natale G, Limanaqi F, Busceti CL, et al. Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS. Front Neurosci. 2021;15:639140. doi:10.3389/fnins.2021.639140
4. Sabia S, Fayosse A, Dumurgier J, et al. Association of sleep duration in middle and old age with incidence of dementia. Nat Comm. 2021;12:2289. doi:10.1038/s41467-021-22354-2
5. García-Aviles JE, Méndez-Hernández R, Guzmán-Ruiz MA, et al. Metabolic Disturbances Induced by Sleep Restriction as Potential Triggers for Alzheimer’s Disease. Front Integr Neurosci. 2021;15:722523. doi:10.3389/fnint.2021.722523