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Cited by 615Alzheimer's disease research and treatmentsSleep and Wakefulness ResearchDementia and Cognitive Impairment Research

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Bidirectional relationship between sleep and Alzheimer’s disease: role of amyloid, tau, and other factors

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Wang, Chanung, Holtzman, David M.·2020·Neuropsychopharmacology
DOI 10.1038/s41386-019-0478-5PMC PMC6879647
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Abstract

As we age, we experience changes in our nighttime sleep and daytime wakefulness. Individuals afflicted with Alzheimer's disease (AD) can develop sleep problems even before memory and other cognitive deficits are reported. As the disease progresses and cognitive changes ensue, sleep disturbances become even more debilitating. Thus, it is imperative to gain a better understanding of the relationship between sleep and AD pathogenesis. We postulate a bidirectional relationship between sleep and the neuropathological hallmarks of AD; in particular, the accumulation of amyloid-β (Aβ) and tau. Our research group has shown that extracellular levels of both Aβ and tau fluctuate during the normal sleep-wake cycle. Disturbed sleep and increased wakefulness acutely lead to increased Aβ production and decreased Aβ clearance, whereas Aβ aggregation and deposition is enhanced by chronic increased wakefulness in animal models. Once Aβ accumulates, there is evidence in both mice and humans that this results in disturbed sleep. New findings from our group reveal that acute sleep deprivation increases levels of tau in mouse brain interstitial fluid (ISF) and human cerebrospinal fluid (CSF) and chronic sleep deprivation accelerates the spread of tau protein aggregates in neural networks. Finally, recent evidence also suggests that accumulation of tau aggregates in the brain correlates with decreased nonrapid eye movement (NREM) sleep slow wave activity. In this review, we first provide a brief overview of the AD and sleep literature and then highlight recent advances in the understanding of the relationship between sleep and AD pathogenesis. Importantly, the effects of the bidirectional relationship between the sleep-wake cycle and tau have not been previously discussed in other reviews on this topic. Lastly, we provide possible directions for future studies on the role of sleep in AD.

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  • Sleep accelerates the removal of amyloid beta protein and tau protein from the brain.

    “Therapies such as zolpidem and suvorexant may improve sleep, and it is increasingly recognized that sleep accelerates the removal of amyloid beta protein and tau protein from the brain. 46”

    From Critical evaluation of real‐world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation (2026) · cites this paper as [46]

    The Sleep and Aβ section says sleep facilitates Aβ clearance from brain interstitial fluid. The Conclusion reports that sleep disturbance changes extracellular levels of both Aβ and tau, but says further studies are needed to determine whether their production and clearance follow similar mechanisms. Thus, the claim that sleep accelerates tau removal is not established by this paper. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Metadata

Authors
Wang, C., & Holtzman, D. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Holtzman, David M.
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2019-08-13
Volume
45
Issue
1
Pages
104-120
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-019-0478-5
PMC
PMC6879647
OpenAlex
W2966973684
Cited by
615
References
71
Citations by year
2026: 90 · 2025: 119 · 2024: 134 · 2023: 109 · 2022: 77 · 2021: 62 · 2020: 21 · 2019: 3
FWCI
4.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
U.S. Department of Health & Human Services | National Institutes of Health (P01NS074969)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, sleep, sleep-wake cycle, amyloid-beta, tau protein, sleep deprivation, wakefulness, bidirectional relationship, interstitial fluid, cerebrospinal fluid, tau aggregation, amyloid-beta clearance, sleep disorders
MeSH terms
Aging, Alzheimer Disease, Animals, Humans, Sleep, Sleep Wake Disorders, Amyloid beta-Peptides, tau Proteins

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