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Peer-reviewedCC BY-NC-NDNeurobiology of Disease

The Glymphatic system: A key mechanism linking sleep to brain health and diseases

  • Zi Yang1
  • Pengtao Li1
  • Rui Yin1
  • Sishuai Sun1
  • Xiaoyu Liu1
  • Congcong Deng1
  • Ziyuan Fang2
  • Yue Wang2
  • Xiao Zhang3
  • Junji Wei4
4 affiliations
  1. 1Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
  2. 2Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College Fudan University, Shanghai, China
  3. 3Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Electronic address: [email protected]
  4. 4Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Electronic address: [email protected]
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Abstract

Sleep is increasingly recognized as a fundamental regulator of brain homeostasis, yet the mechanisms linking sleep to neurological health have only recently begun to emerge. The glymphatic system, a brain-wide perivascular transport network, has provided a mechanistic framework connecting sleep physiology with brain health and disease. Accumulating evidence indicates that glymphatic activity is markedly enhanced during sleep through coordinated regulation of vasomotion, norepinephrine oscillations, aquaporin-4 polarization, extracellular space expansion, respiration, and meningeal lymphatic drainage. Conversely, chronic sleep disruption impairs glymphatic transport, promotes the accumulation of neurotoxic metabolites, and contributes to neuroinflammation, thereby accelerating the progression of diverse neurological disorders. In this review, we integrate recent advances in glymphatic biology from structural organization and transport mechanisms to sleep-dependent regulation and emerging neuroimaging approaches. We critically evaluate current evidence supporting glymphatic dysfunction in neurodegenerative diseases, traumatic brain injury, cerebrovascular disorders, psychiatric disorders, brain tumors, and ocular diseases, highlighting sleep-related impairment as a common mechanistic denominator. Particular emphasis is placed on the translational potential and limitations of non-invasive imaging biomarkers, including DTI-ALPS, dynamic contrast-enhanced MRI, diffusion MRI, PET, and emerging multimodal techniques. We also discuss major controversies surrounding glymphatic physiology, including the relative contributions of bulk flow and diffusion, species-specific differences, and the challenges of validating human imaging biomarkers. Finally, we propose a conceptual sleep-glymphatic-disease axis that integrates current mechanistic knowledge with clinical translation. Understanding how sleep regulates glymphatic function may provide new opportunities for disease prevention, biomarker development, and therapeutic intervention across a broad spectrum of brain disorders.

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Cite

BibTeXRIS
BibTeX
@article{yang2026glymphatic,
  title = {{The Glymphatic system: A key mechanism linking sleep to brain health and diseases}},
  author = {Zi Yang and Pengtao Li and Rui Yin and Sishuai Sun and Xiaoyu Liu and Congcong Deng and Ziyuan Fang and Yue Wang and Xiao Zhang and Junji Wei},
  journal = {Neurobiology of Disease},
  year = {2026},
  month = jul,
  doi = {10.1016/j.nbd.2026.107515},
  url = {https://doi.org/10.1016/j.nbd.2026.107515},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - The Glymphatic system: A key mechanism linking sleep to brain health and diseases
AU  - Zi Yang
AU  - Pengtao Li
AU  - Rui Yin
AU  - Sishuai Sun
AU  - Xiaoyu Liu
AU  - Congcong Deng
AU  - Ziyuan Fang
AU  - Yue Wang
AU  - Xiao Zhang
AU  - Junji Wei
PY  - 2026
DA  - 2026/07/08
JO  - Neurobiology of Disease
DO  - 10.1016/j.nbd.2026.107515
UR  - https://doi.org/10.1016/j.nbd.2026.107515
AB  - Sleep is increasingly recognized as a fundamental regulator of brain homeostasis, yet the mechanisms linking sleep to neurological health have only recently begun to emerge. The glymphatic system, a brain-wide perivascular transport network, has provided a mechanistic framework connecting sleep physiology with brain health and disease. Accumulating evidence indicates that glymphatic activity is markedly enhanced during sleep through coordinated regulation of vasomotion, norepinephrine oscillations, aquaporin-4 polarization, extracellular space expansion, respiration, and meningeal lymphatic drainage. Conversely, chronic sleep disruption impairs glymphatic transport, promotes the accumulation of neurotoxic metabolites, and contributes to neuroinflammation, thereby accelerating the progression of diverse neurological disorders. In this review, we integrate recent advances in glymphatic biology from structural organization and transport mechanisms to sleep-dependent regulation and emerging neuroimaging approaches. We critically evaluate current evidence supporting glymphatic dysfunction in neurodegenerative diseases, traumatic brain injury, cerebrovascular disorders, psychiatric disorders, brain tumors, and ocular diseases, highlighting sleep-related impairment as a common mechanistic denominator. Particular emphasis is placed on the translational potential and limitations of non-invasive imaging biomarkers, including DTI-ALPS, dynamic contrast-enhanced MRI, diffusion MRI, PET, and emerging multimodal techniques. We also discuss major controversies surrounding glymphatic physiology, including the relative contributions of bulk flow and diffusion, species-specific differences, and the challenges of validating human imaging biomarkers. Finally, we propose a conceptual sleep-glymphatic-disease axis that integrates current mechanistic knowledge with clinical translation. Understanding how sleep regulates glymphatic function may provide new opportunities for disease prevention, biomarker development, and therapeutic intervention across a broad spectrum of brain disorders.
SN  - 0969-9961
SN  - 1095-953X
ER  -