Jared Eichner

Introduction: The glymphatic system is a recently discovered waste clearance system utilizing a perivascular channel system to eliminate waste from the central nervous system.¹ Sporadic Alzheimer’s disease (SAD) does not have a clear genetic cause. However, multiple lifestyle factors, including reduced sleep, could influence the development of SAD.² Studies linking impaired sleep, and the accumulation of SAD biomarkers have furthered interest into sleep and the glymphatic system’s role in SAD.^3,4 A recent human study, examining the factors affecting the glymphatic system, has been pivotal in understanding how this system could be enhanced to optimize clearance of neuronal waste and prevent SAD.⁵ Methods: One murine and human study used PET imaging and 18F-florbetaben to identify brain regions where beta-amyloid (Aβ) deposited after one night of rested sleep and one night of sleep deprivation.³ Another study quantified ISF and CSF tau in mice and humans after sleep deprivation. The mouse study utilized a chemogenetic approach to induce sleep deprivation for one day, and the humans were kept awake for one night without stimulants.⁴ A third study used blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI), electroencephalogram (EEG), and traditional fMRI to monitor and analyze different parameters throughout the day and night of human subjects.⁵ Results: Mice revealed Aβ accumulation in the brain regions associated with Alzheimer’s pathogenesis after one night of sleep deprivation, indicating that impaired sleep may contribute to SAD development.³ This hypothesis was substantiated by a study which showed that accumulation of tau in the interstitial fluid (ISF) increases greatly in sleep-deprived mice in comparison to the control group, and the tau accumulation in the cerebrospinal fluid (CSF) of sleep-deprived humans was 50% greater than for the control group.⁴ The human study revealed insight into the factors contributing to the clearance of waste products from the brain.⁵ Over a 40-second time course during stage 3 slow-wave sleep, CSF oscillations coupled to slow-delta brain waves and arterial pulsations, with CSF influx only functioning during this sleep cycle segment.⁵ Conclusions: These studies suggest additional inquiry might be warranted into whether deeper sleep could reduce the incidence, or even slow down the progression, of AD,⁵ and whether there could be pharmacological approaches for clearing the glymphatic flow via increased CSF oscillations.⁶ Increased CSF influx into the brain is linked to sleep, supports the clearance of ISF through the glymphatic system and could thereby act as an agent in the development and prevention of SAD.⁵

1. Mestre H, Tithof J, Du T, et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun. 2018;9(1):4878. doi:10.1038/s41467-018-07318-3.
2. Casaletto KB, Staffaroni AM, Wolf A, et al. Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.  Alzheimers Dement. 2020;16(1):91-105. doi:10.1002/alz.12001.
3. Shokri-Kojori E, Wang G-J, Wiers CE, et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci. 2018;115(17):4483-4488. doi:10.1073/pnas.1721694115.
4. Holth JK, Fritschi SK, Wang C, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019;363(6429):880-884. doi:10.1126/science.aav2546.
5. Fultz NE, Bonmassar G, Setsompop K, et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019;366(6465):628-631. doi:10.1126/science.aax5440.
6. Hablitz LM, Vinitsky HS, Sun Q, et al. Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv. 2019;5(2). doi:10.1126/sciadv.aav5447.