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Cited by 1,145Cerebrospinal fluid and hydrocephalusSleep and Wakefulness ResearchAlzheimer's disease research and treatments

Glymphatic failure as a final common pathway to dementia

Open access
Nedergaard, Maiken, Goldman, Steven A.·2020·Science
DOI 10.1126/science.abb8739PMC PMC8186542
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Abstract

Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that sleep-dependent glymphatic clearance fails with aging and neurodegenerative disease, allowing protein waste to stagnate and aggregate. It argues that glymphatic failure may be a shared, therapeutically targetable final pathway linking sleep disruption, vascular disease, and dementia.

Key findings

  • Glymphatic transport is active mainly during NREM sleep and correlates with slow-wave activity; it declines with age and disease. In aged wild-type mice, influx of larger CSF tracers fell by as much as 85%, and human contrast clearance was inversely related to age.
  • Protein aggregation may be driven by stagnant extracellular flow rather than solely by synaptic spread. The regional patterns of amyloid-beta, tau, and alpha-synuclein deposition overlap with glymphatic CSF inflow routes and with trapping of intrathecal contrast agents.
  • AQP4 water channels in astrocytic endfeet are required for glymphatic flow. AQP4 deletion worsened amyloid plaques and memory deficits in APP/PS1 mice, and human AQP4 variants have been linked to sleep slow-wave activity, daytime sleepiness, amyloid burden, and rate of cognitive decline.
  • Cardiovascular pulsatility helps drive CSF movement. Hypertension, small vessel disease, heart failure, and diabetes are associated with impaired glymphatic transport, potentially connecting vascular dementia and Alzheimer’s disease.

Methods

  • Review/synthesis, not primary research. It integrates rodent and human studies on sleep, glymphatic and meningeal lymphatic clearance, AQP4, protein aggregation, and cardiovascular disease.
  • The main analysis is conceptual: it compares published findings on glymphatic flow, aggregate spread, and vascular risk to propose a final common pathway. No new data, sample, or statistical analysis are reported.

Limitations

  • The authors state that CNS flow vectors remain incompletely understood and more work is needed to account for all clearance paths; it is unclear whether oligomers or larger aggregates are the principal toxic species; and future work should determine whether sleep disturbances before diagnosis contribute to seeding and whether later sleep disturbances accelerate spread.
  • Evident from the text: as a review, it relies on cited animal models and human observational/imaging studies, and several central claims—such as glymphatic failure as a causal final pathway and as a therapeutic target—are presented as hypotheses rather than tested in the paper.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1126/science.abb8739

Cites

116 of 116 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 146 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The glymphatic system degrades with age.

    “Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias.”
    • Also stated in: § Why do proteins aggregate in neurodegenerative diseases? · plain
      “The decrease in glymphatic flow in old mice is in part mediated by mislocation of AQP4 water channels away from the vascular wall (52)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Kress BT, Impairment of paravascular clearance pathways in the aging brain. Annals of neurology 76, 845– 861 (2014). 25204284 PMC4245362 source

      Not checked in the free run.

  • Interpretationreasoning

    Sleep disturbance is causally related to symptomatic progression in neurodegenerative dementias.

    “suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Glymphatic failure may be a therapeutically targetable final common pathway for neurodegenerative diseases.

    “for which glymphatic failure may comprise a therapeutically targetable final common pathway”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Glymphatic flow appears to stop with the onset of wakefulness.

    “Fluid flow through the glymphatic system is thus inextricably linked with sleep, to the extent that flow appears to stop with the onset of wakefulness.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source

      Not checked in the free run.

    • cites [36] Hablitz LM, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5, eaav5447 (2019). 30820460 PMC6392807 source

      Not checked in the free run.

  • Premisecitation

    Meningeal lymphatic vessels in the dura drain brain interstitial CSF.

    “two other groups reported that classical lymphatic vessels draining brain interstitial CSF might also be identified in the dura – the fibrous external layer of the meningeal membranes (39, 40).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] Louveau A, Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337– 341 (2015). 26030524 PMC4506234 source

      Not checked in the free run.

    • cites [40] Aspelund A, A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. The Journal of experimental medicine 212, 991– 999 (2015). 26077718 PMC4493418 source

      Not checked in the free run.

  • May combine two claims. 52
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Premisecitation

    Sleep quality declines with age, and disrupted sleep architecture frequently precedes dementia onset in neurodegenerative diseases.

    “The quality of sleep decreases as we age and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases.”
    • Also stated in: § Sleep, aging, neurodegeneration and the glymphatic system · plain
      “Most NREM sleep in people over 60 years is light, consisting of the more superficial stages 1–2 (79)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [79] Landolt HP, Borbely AA, Age-dependent changes in sleep EEG topography. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 112, 369– 377 (2001). 11165543 source

      Not checked in the free run.

    • cites [80] Malhotra RK, Neurodegenerative Disorders and Sleep. Sleep medicine clinics 13, 63– 70 (2018). 29412984 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The glymphatic system is a cerebrospinal fluid transport system that shares functions with peripheral lymphatic vessels, including export of excess interstitial fluid and proteins.

    “The glymphatic system is a highly organized cerebrospinal fluid transport system that shares several key functions with the lymphatic vessels of peripheral tissues, including the export of excess interstitial fluid and proteins”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Iliff JJ, A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine 4, 147ra 111 (2012). PMC3551275 22896675 source

      Not checked in the free run.

    • Rests on an assumption: For brain homeostasis, protein clearance must approximately equal protein synthesis.

  • May combine two claims.

    Premisecitation

    Brain fluid clearance occurs through glymphatic perivascular spaces formed by astrocytic vascular endfeet, because the brain lacks histologically distinct lymphatic vessels.

    “Yet brain tissue itself lacks histologically-distinct lymphatic vessels. Rather, fluid clearance from the brain proceeds via the glymphatics, a structurally distinct system of fluid transport that utilizes the perivascular spaces created by the vascular endfeet of astrocytes (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Simard M, Arcuino G, Takano T, Liu QS, Nedergaard M, Signaling at the gliovascular interface. The Journal of neuroscience: the official journal of the Society for Neuroscience 23, 9254– 9262 (2003). 14534260 PMC6740832 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The glymphatic system clears protein waste from the brain and is mostly active during sleep.

    “The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep.”
    • Also stated in: § The glymphatic and lymphatic systems · plain
      “fluid transport is enabled by sleep and suppressed during wakefulness”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source

      Not checked in the free run.

    • cites [36] Hablitz LM, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5, eaav5447 (2019). 30820460 PMC6392807 source

      Not checked in the free run.

    • Rests on an assumption: For brain homeostasis, protein clearance must approximately equal protein synthesis.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Sleep deprivation increases EEG slow wave activity during recovery sleep.

    “the antecedent sleep loss can be identified post hoc by an increase in EEG slow wave activity during recovery sleep (8)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Rodriguez AV, Why Does Sleep Slow-Wave Activity Increase After Extended Wake? Assessing the Effects of Increased Cortical Firing During Wake and Sleep. The Journal of neuroscience: the official journal of the Society for Neuroscience 36, 12436– 12447 (2016). 27927960 PMC5148229 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glymphatic clearance is enabled by sleep and suppressed during wakefulness.

    “glymphatic clearance is temporally regulated and cyclically so, in that fluid transport is enabled by sleep and suppressed during wakefulness.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source

      Not checked in the free run.

    • cites [36] Hablitz LM, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5, eaav5447 (2019). 30820460 PMC6392807 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Waste removal is likely most efficient in the early hours of sleep and especially during recovery sleep after prolonged wakefulness.

    “As such, waste removal is likely most efficient in the early hours of sleep, and especially during recovery sleep after prolonged wakefulness (37).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Hauglund L, Pavan C, Nedergaard M, Cleaning the sleeping brain – the potential restorative function of the glymphatic system. Current Opinion in Physiology 15 1– 6 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The circadian rhythm of glymphatic flow is supported by temporally regulated AQP4 localization via the dystrophin-associated complex, linking to the molecular circadian clock.

    “This rhythm is supported by the temporally-regulated localization of AQP4 via the dystrophin associated complex, providing a dynamic link to the molecular circadian clock (38),”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Hablitz L, Circadian control of brain glymphatic/lymphatic fluid flow. Nature communications (in press), (2020). PMC7468152 32879313 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Astrocytic endfeet are connected by gap junctions, and about half of their plasma membrane facing the vessel wall contains AQP4 square arrays.

    “The astrocytic endfeet are connected by gap junctions, and almost 50% of their plasma membrane facing the vessel wall is occupied by square arrays composed of the water channel AQP4 (29).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Nagelhus EA, Ottersen OP, Physiological roles of aquaporin-4 in brain. Physiological reviews 93, 1543– 1562 (2013). 24137016 PMC3858210 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of AQP4 reduces CSF tracer influx and solute efflux from the neuropil.

    “Deletion of AQP4 channels reduces both the influx of CSF tracers and the efflux of solutes from the neuropil (24, 30, 31).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Iliff JJ, A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine 4, 147ra 111 (2012). PMC3551275 22896675 source

      Not checked in the free run.

    • cites [30] Mestre H, Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7, (2018). PMC6307855 30561329 source

      Not checked in the free run.

    • cites [31] Mestre H, Cerebrospinal fluid influx drives acute ischemic tissue swelling. Science 367, (2020). PMC7375109 32001524 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glymphatic fluid transport is directionally polarized: influx along penetrating arteries, AQP4-supported entry into neuropil, and efflux along peri-venous spaces and cranial and spinal nerves.

    “fluid transport through the glymphatic system is directionally polarized, with influx along penetrating arteries, fluid entry into the neuropil supported by AQP4, and efflux along the peri-venous spaces, as well as along the cranial and spinal nerves (24, 32–34).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [24] Iliff JJ, A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine 4, 147ra 111 (2012). PMC3551275 22896675 source

      Not checked in the free run.

    • cites [32] Braun M, Iliff JJ, The impact of neurovascular, blood-brain barrier, and glymphatic dysfunction in neurodegenerative and metabolic diseases. International review of neurobiology 154, 413– 436 (2020). 32739013 source

      Not checked in the free run.

    • cites [33] Wang X, An ocular glymphatic clearance system removes beta-amyloid from the rodent eye. Science translational medicine 12, (2020). PMC7356596 32213628 source

      Not checked in the free run.

    • cites [34] Mestre H, Mori Y, Nedergaard M, The Brain’s Glymphatic System: Current Controversies. Trends in neurosciences, (2020). PMC7331945 32423764 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Brain fluid transport initiates and proceeds during NREM sleep, and CSF tracer influx correlates with EEG slow wave activity prevalence.

    “Brain fluid transport initiates and proceeds during NREM sleep, and CSF tracer influx correlates with the prevalence of EEG slow wave activity (35, 36).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source

      Not checked in the free run.

    • cites [36] Hablitz LM, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5, eaav5447 (2019). 30820460 PMC6392807 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glymphatic flow is regulated by circadian rhythmicity, peaking during the sleep phase of diurnal activity and falling during the active phase, independent of the light cycle.

    “A recent analysis showed that glymphatic flow is also regulated by circadian rhythmicity, such that fluid transport peaks during the sleep phase of diurnal activity, and falls during the active phase, independent of the light cycle.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Hablitz L, Circadian control of brain glymphatic/lymphatic fluid flow. Nature communications (in press), (2020). PMC7468152 32879313 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UV photoablation of meningeal lymphatic vessels and mechanical ligation of cervical lymphatics aggravated amyloid plaque formation in mouse models of Alzheimer disease.

    “Conversely, both UV photoablation of meningeal lymphatic vessels and mechanical ligation of cervical lymphatics aggravated amyloid plaque formation in the same mouse models of Alzheimer disease (50, 51).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Da Mesquita S, Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185– 191 (2018). 30046111 PMC6085146 source

      Not checked in the free run.

    • cites [51] Wang L, Deep cervical lymph node ligation aggravates AD-like pathology of APP/PS1 mice. Brain pathology 29, 176– 192 (2019). 30192999 PMC8028636 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    VEGFC overexpression induced sprouting of meningeal lymphatic vessels and slowed cognitive decline in a mouse model of Alzheimer disease.

    “VEGFC-overexpression induced spouting of the meningeal lymphatic vessels and slowed the cognitive decline in a mouse model of Alzheimer disease (50).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Da Mesquita S, Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185– 191 (2018). 30046111 PMC6085146 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The glymphatic and meningeal lymphatic systems are connected, and CSF tracers exit the CNS via meningeal lymphatic vessels, especially ventral lymph vessels draining to cervical lymph nodes.

    “Yet the glymphatic and meningeal lymphatic systems are clearly connected: CSF tracers can exit the CNS via the meningeal lymphatic vessels, particularly by way of the lymph vessels draining the ventral aspect of the brain draining to the cervical lymph nodes (39, 40, 42).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [39] Louveau A, Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337– 341 (2015). 26030524 PMC4506234 source

      Not checked in the free run.

    • cites [40] Aspelund A, A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. The Journal of experimental medicine 212, 991– 999 (2015). 26077718 PMC4493418 source

      Not checked in the free run.

    • cites [42] Ahn JH, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62– 66 (2019). 31341278 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a murine Alzheimer disease model, amyloid-β is present at high concentrations in cervical and axillary lymph nodes, at levels analogous to brain, and is undetectable or barely detectable in spleen and other peripheral tissues.

    “in a murine model of Alzheimer disease, amyloid-b was present in high concentrations in the cervical and axillary lymph nodes, at levels analogous to those in the brain, and yet was either undetectable or barely so in the spleen and other peripheral tissues (47).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Pappolla M, Evidence for lymphatic Abeta clearance in Alzheimer’s transgenic mice. Neurobiology of disease 71, 215– 219 (2014). 25102344 PMC5589075 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CSF exit via meningeal lymph vessels and cranial and spinal nerve roots is rapid, with contrast agents detected in deep cervical lymph nodes within minutes after CSF delivery.

    “CSF exit from the CNS by way of the meningeal lymph vessels, as well as via both cranial and spinal nerve roots, is rapid; contrast agents can be detected in the deep cervical lymph nodes within minutes after CSF delivery (42–45).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [42] Ahn JH, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62– 66 (2019). 31341278 source

      Not checked in the free run.

    • cites [43] Ma Q, Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain. Acta neuropathologica 137, 151– 165 (2019). 30306266 PMC6338719 source

      Not checked in the free run.

    • cites [44] Ma Q, Decker Y, Muller A, Ineichen BV, Proulx ST, Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels. The Journal of experimental medicine 216, 2492– 2502 (2019). 31455602 PMC6829589 source

      Not checked in the free run.

    • cites [45] Jacob L, Anatomy and function of the vertebral column lymphatic network in mice. Nature communications 10, 4594 (2019). PMC6785564 31597914 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glymphatic CSF influx and CSF clearance are reduced in early amyloid deposition in the APP/PS1 Alzheimer disease model compared with littermate controls, and CSF clearance continues to decline as amyloid burden increases.

    “glymphatic CSF influx and CSF clearance are each reduced in early stages of amyloid deposition in the APP/PS1 model of Alzheimer disease, compared with littermate controls; CSF clearance continues to decline as the amyloid burden increases (Fig. 1b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Da Mesquita S, Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185– 191 (2018). 30046111 PMC6085146 source

      Not checked in the free run.

    • cites [55] Peng W, Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiology of disease 93, 215– 225 (2016). 27234656 PMC4980916 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The suppressive effects of age and amyloid-β overexpression on glymphatic flow extend to other rodent neurodegeneration models; traumatic brain injury and Parkinson's disease are linked to sustained reduction of glymphatic fluid transport.

    “The suppressive effects of both age and amyloid-ß overexpression on glymphatic flow can be extended to other experimental rodent models of neurodegeneration; both traumatic brain injury and Parkinson’s disease are similarly linked to a sustained reduction of glymphatic fluid transport (56–58).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [56] Iliff JJ, Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 16180– 16193 (2014). 25471560 PMC4252540 source

      Not checked in the free run.

    • cites [57] Zou W, Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated alpha-synuclein. Translational neurodegeneration 8, 7 (2019). 30867902 PMC6396507 source

      Not checked in the free run.

    • cites [58] Sundaram S, Establishing a framework for neuropathological correlates and glymphatic system functioning in Parkinson’s disease. Neuroscience and biobehavioral reviews 103, 305– 315(2019). 31132378 PMC6692229 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The decrease in glymphatic flow in old mice is partly mediated by mislocation of AQP4 away from the vascular wall and possibly by atrophy of meningeal lymphatic vessels.

    “The decrease in glymphatic flow in old mice is in part mediated by mislocation of AQP4 water channels away from the vascular wall (52) and possible by atrophy of meningeal lymphatic vessel (42).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Kress BT, Impairment of paravascular clearance pathways in the aging brain. Annals of neurology 76, 845– 861 (2014). 25204284 PMC4245362 source

      Not checked in the free run.

    • cites [42] Ahn JH, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62– 66 (2019). 31341278 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The hallmark feature of proteinopathies is fibrillary aggregates of misfolded or hyperphosphorylated proteins.

    “The hallmark feature of these proteinopathies are the fibrillary aggregates of misfolded or hyperphosphorylated proteins (59).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Soto C, Unfolding the role of protein misfolding in neurodegenerative diseases. Nature reviews. Neuroscience 4, 49– 60 (2003). 12511861 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aggregate spread happens in both antero- and retrograde directions across regions that are anatomical neighbors, weakening arguments for synaptic spread.

    “The arguments for synaptic spread are somewhat weakened by the fact that aggregate spread happens in both antero- and retrograde directions across regions that are anatomical neighbors (68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Henderson MX, Spread of alpha-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nature neuroscience 22, 1248– 1257 (2019). 31346295 PMC6662627 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Specific misfolded and aggregated proteins can propagate and spread in a prion-like fashion.

    “The recent discovery that specific misfolded and aggregated proteins can propagate and spread in a prion-like fashion has sparked considerable interest (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Jucker M, Walker LC, Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45– 51 (2013). 24005412 PMC3963807 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Interpretationcitation

    An alternative hypothesis is that aggregates spread via extracellular spaces, and age-dependent reduction in glymphatic flow with fluid stagnation raises local protein concentration to a level favoring aggregation.

    “An alternative hypothesis is that aggregates simply spread via the extracellular spaces, and that the age-dependent reduction in glymphatic flow, with its attendant fluid stagnation, raises the local protein concentration to a level that favors aggregation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Aggregation-prone proteins include amyloid-β in Alzheimer disease; phosphorylated tau in frontotemporal dementia, chronic traumatic encephalopathy, and Alzheimer's; α-synuclein in Parkinson's, Lewy body disease, and multisystem atrophies; mutant huntingtin in Huntington's disease; and TDP-43 in ALS and frontotemporal dementia.

    “These aggregation-prone proteins include amyloid-ß in Alzheimer Disease; phosphorylated tau in frontotemporal dementia (FTD) and chronic traumatic encephalopathy, as well as in Alzheimer’s; α-synuclein in Parkinson’s, Lewy body disease, and the multisystem atrophies; mutant huntingtin in Huntington’s disease, and TDP-43 in ALS and FTD (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Although specific protein species differ across neurodegenerative disorders, in most cases their aggregates are formed in part by interactions of intermolecular β-sheet-rich strands.

    “Although the specific protein species differ in the different neurodegenerative disorders, in most cases their protein aggregates are formed in part by the interactions of intermolecular β-sheet-rich strands.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A lack of fluid flow (stagnation) or shear stress can promote aggregation, which can occur at a distance from the protein source, for example along the cerebral vasculature.

    “A lack of fluid flow, i.e. stagnation, or its opposite, shear stress, can also promote aggregation (64, 65), which can occur at a distance from the protein source - for example, along the cerebral vasculature (Fig. 1) (66).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [64] Trumbore CN, Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes. Journal of Alzheimer’s disease: JAD 54, 457– 470 (2016). 27567812 PMC5026135 source

      Not checked in the free run.

    • cites [65] Roeters SJ, Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy. Scientific reports 7, 41051 (2017). 28112214 PMC5253669 source

      Not checked in the free run.

    • cites [66] Weller RO, Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. Journal of neuropathology and experimental neurology 57, 885– 894 (1998). 9786239 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuroimaging studies from the Eide group show that intrathecally delivered contrast agents first enter the brain along large cerebral arteries, reaching mediobasal frontal lobe and cingulate cortex via the anterior cerebral artery, insula via the middle cerebral artery, and limbic structures including hippocampus and entorhinal cortex via the posterior circulation.

    “Neuroimaging studies from the Eide group have shown that intrathecally-delivered contrast agents first are propelled into the brain along the large cerebral arteries entering the mediobasal frontal lobe and cingulate cortex along the anterior cerebral artery, insula via the middle cerebral artery and the limbic structures, including the hippocampus and entorhinal cortex via the posterior cir”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Ringstad G, Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI insight 3, (2018). PMC6124518 29997300 source

      Not checked in the free run.

    • cites [75] Ringstad G, Vatnehol SAS, Eide PK, Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain: a journal of neurology 140, 2691– 2705 (2017). 28969373 PMC5841149 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Alzheimer disease, amyloid-β deposition typically first occurs in basal portions of frontal, temporal, and occipital lobes, later spreads to hippocampus and posterior parietal cortex, initially sparing motor and sensory cortex, and finally recruits these regions and subcortical gray matter.

    “In Alzheimer disease, amyloid-ß deposition typically first deposit in the basal portions of the frontal, temporal, and occipital lobes. Later the plaques spread to include the hippocampus and posterior parietal cortex, initially sparing both the motor and sensory cortex. These latter regions are first recruited in the final stages of the disease, along with subcortical gray matter regions.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Hong S, Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712– 716 (2016). 27033548 PMC5094372 source

      Not checked in the free run.

    • cites [72] Terada T, In vivo direct relation of tau pathology with neuroinflammation in early Alzheimer’s disease. Journal of neurology 266, 2186– 2196 (2019). 31139959 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These proteins lack N-terminal signal sequences, so unconventional mechanisms must be responsible for their release.

    “These proteins all lack N-terminal signal sequences, so that unconventional mechanisms must be responsible for their release (76).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Davis AA, Leyns CEG, Holtzman DM, Intercellular Spread of Protein Aggregates in Neurodegenerative Disease. Annual review of cell and developmental biology 34, 545– 568 (2018). PMC6350082 30044648 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The aged brain spends less time in NREM sleep, potentially causing a catastrophic decline in clearance of brain waste, because glymphatic fluid transport efficacy correlates directly with slow wave activity prevalence.

    “Thus, the aged brain spends less time in NREM sleep, potentially causing a catastrophic decline in clearance of brain waste, as the efficacy of glymphatic fluid transport correlates directly with the prevalence of slow wave activity (36).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Hablitz LM, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5, eaav5447 (2019). 30820460 PMC6392807 source

      Not checked in the free run.

    • cites [79] Landolt HP, Borbely AA, Age-dependent changes in sleep EEG topography. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 112, 369– 377 (2001). 11165543 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Several studies have highlighted the critical role of oligomers as both directly toxic and as niduses for macromolecular aggregation.

    “several studies have highlighted the critical role of oligomers as both directly toxic, and as niduses for macromolecular aggregation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proteins involved in neurodegenerative diseases may normally be intracellular or extracellular, but all are present in the extracellular space.

    “while proteins involved in neurodegenerative diseases may normally be either intracellular or extracellular in nature, all are present in the extracellular space.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Davis AA, Leyns CEG, Holtzman DM, Intercellular Spread of Protein Aggregates in Neurodegenerative Disease. Annual review of cell and developmental biology 34, 545– 568 (2018). PMC6350082 30044648 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Older individuals rarely enter deep NREM stage 3 sleep; most NREM sleep in people over 60 years is light, consisting of superficial stages 1-2.

    “Perhaps more critically, older individuals rarely enter deep NREM, stage 3 sleep. Most NREM sleep in people over 60 years is light, consisting of the more superficial stages 1–2 (79)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Landolt HP, Borbely AA, Age-dependent changes in sleep EEG topography. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 112, 369– 377 (2001). 11165543 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sleep quality decreases as a function of normal aging; insomnia is more frequent with age, and total sleep duration becomes shorter and more interrupted.

    “sleep quality decreases as a function of normal aging. Insomnia is more frequent with age, and total sleep duration becomes shorter and more interrupted.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Landolt HP, Borbely AA, Age-dependent changes in sleep EEG topography. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 112, 369– 377 (2001). 11165543 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The failure of immune therapies to clear amyloid-β in Alzheimer patients may reflect relatively late initiation of treatment or insufficient antibody load to clear enough amyloid-β for clinical benefit.

    “The failure of these clinical trials may reflect the relatively late initiation of treatment or that the antibody load was not enough to clear sufficient amyloid-ß to yield clinical benefit.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Knopman DS, Sifting through a failed Alzheimer trial: What biomarkers tell us about what happened. Neurology 90, 447– 448 (2018). 29429973 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cardiovascular fitness positively correlates with cognition in young adults and preserves cognitive performance with aging.

    “while cardiovascular fitness positively correlates with cognition in young adults (89) and preserves cognitive performance with aging (90).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Aberg MAI, Cardiovascular fitness is associated with cognition in young adulthood. Proceedings of the National Academy of Sciences of the United States of America 106, 20906– 20911 (2009). 19948959 PMC2785721 source

      Not checked in the free run.

    • cites [90] Wendell CR, Cardiorespiratory fitness and accelerated cognitive decline with aging. J Gerontol A Biol Sci Med Sci 69, 455– 462 (2014). 24192540 PMC3968827 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The integrity of perivascular AQP4 localization degrades with Alzheimer disease, while it is preserved in subjects older than 85 years who remained cognitively intact.

    “Structurally, the integrity of perivascular AQP4 localization was found to degrade with AD, while it was preserved by subjects older than 85 years, who remained cognitively intact (84).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Zeppenfeld DM, Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains. JAMA neurology 74, 91– 99 (2017). 27893874 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with two specific AQP4 SNPs exhibited slower cognitive decline after Alzheimer disease diagnosis, while cognitive decline progressed more rapidly in subjects with two other AQP4 SNPs.

    “Patients with two specific AQP4 SNPs exhibited slower cognitive decline after AD diagnosis, while conversely, cognitive decline progressed more rapidly in subjects with two other AQP4 SNPs (85).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Burfeind KG, The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer’s disease. Alzheimer’s & dementia 3, 348– 359 (2017). PMC5651426 29067342 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, genetic variation in AQP4 impacts both sleep and amyloid-β burden.

    “In man, genetic variation in AQP4 has been shown to impact both sleep and amyloid-β burden (82).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Rainey-Smith SR, Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden. Translational psychiatry 8, 47 (2018). 29479071 PMC5865132 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Targeting the brain's waste removal system may be an attractive approach for alleviating the waste burden of proteinopathies, because aggregation-prone proteins are removed by bulk flow without the requirement for specific transporters.

    “Targeting the brain’s waste removal system may thus an attractive approach for alleviating the waste burden of the proteinopathies, because aggregation-prone proteins are removed by bulk flow, without the requirement for specific transporters.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: For brain homeostasis, protein clearance must approximately equal protein synthesis.

  • May combine two claims.

    Interpretationcitation

    Although AQP4 is expressed only in astrocytes and not in amyloid-producing neurons, considerable evidence indicates that AQP4 modulates sleep architecture, tolerance to sleep deprivation, amyloid-β accumulation, and progression of Alzheimer disease.

    “Thus, although AQP4 is expressed only in astrocytes, and not in amyloid-producing neurons, considerable evidence indicates that AQP4 modulates both sleep architecture, the tolerance to sleep deprivation, amyloid-ß accumulation, and the progression of Alzheimer disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SVD is common in hypertensive patients (many also diabetic or smokers) and progresses silently for years before dementia is clinically evident.

    “SVD is common in hypertensive patients, many of whom are concurrently diabetic or smokers, and it progresses silently for years before dementia is clinically evident (99).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Wardlaw JM, Smith C, Dichgans M, Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. The Lancet. Neurology 12, 483– 497 (2013). 23602162 PMC3836247 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Cognitive decline in patients with low cardiac ejection fraction may also reflect poor glymphatic flow and incomplete waste clearance, predisposing to aggregate formation and further slowing of glymphatic flow.

    “Indeed, the cognitive decline frequently noted in patients with low cardiac ejection fraction, so often attributed to low cerebral perfusion, may also reflect poor glymphatic flow and incomplete waste clearance, as well as a consequent predisposition to aggregate formation and still-slower glymphatic flow as a result (95).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Vogels RL, Profile of cognitive impairment in chronic heart failure. Journal of the American Geriatrics Society 55, 1764– 1770 (2007). 17727641 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Sleep quality is compromised in cardiovascular diseases, perhaps providing a link to impaired glymphatic clearance and subsequent protein aggregation and dementia.

    “It is also well-establish that the quality of sleep is compromised in cardiovascular diseases (93) perhaps providing a link to impaired glymphatic clearance and subsequent protein aggregation and dementia (94).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [93] Gonzaga C, Bertolami A, Bertolami M, Amodeo C, Calhoun D, Obstructive sleep apnea, hypertension and cardiovascular diseases. Journal of human hypertension 29, 705– 712 (2015). 25761667 source

      Not checked in the free run.

    • cites [94] Mestre H, Kostrikov S, Mehta RI, Nedergaard M, Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clinical science 131, 2257– 2274 (2017). 28798076 PMC5567781 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SVD is a vascular disorder targeting small cerebral vessels, with progressive thickening of penetrating arteriole walls.

    “Small vessel disease (SVD) is a vascular disorder that targets the small cerebral vessels, in which penetrating arterioles undergo progressive thickening of their walls (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Wardlaw JM, Smith C, Dichgans M, Small vessel disease: mechanisms and clinical implications. The Lancet. Neurology 18, 684– 696 (2019). 31097385 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deterioration of the vascular bed may occur alone or with other pathologies, leading to progressive demyelination and white matter loss.

    “Deterioration of the vascular bed may occur alone or in combination with other pathologies (97), leading to progressive demyelination and loss of white matter (98).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [97] Iadecola C, The pathobiology of vascular dementia. Neuron 80, 844– 866 (2013). 24267647 PMC3842016 source

      Not checked in the free run.

    • cites [98] Zlokovic BV, Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nature reviews. Neuroscience 12, 723– 738 (2011). 22048062 PMC4036520 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypertension induces hypertrophy of vascular smooth muscle cells and arterial wall stiffening, dampening pulsatility and compliance, reducing convective perivascular flow.

    “Hypertension in particular induces hypertrophy of vascular smooth muscle cells, with a stiffening of the arterial wall that dampens arterial wall pulsatility and compliance, thus reducing convective perivascular flow (94, 100).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Mestre H, Kostrikov S, Mehta RI, Nedergaard M, Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clinical science 131, 2257– 2274 (2017). 28798076 PMC5567781 source

      Not checked in the free run.

    • cites [100] Wardlaw JM, Perivascular spaces in the brain: anatomy, physiology and pathology. Nature reviews. Neurology 16, 137– 153 (2020). 32094487 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationcitation

    These processes are linked by regulation of the brain's glymphatic system; directed regulation may offer therapeutic opportunities for disease-modifying treatment.

    “These various processes are linked in their regulation by the brain’s glymphatic system, whose directed regulation in turn may present bold new therapeutic opportunities for the disease-modifying treatment of patients with these disorders (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Ringstad G, Vatnehol SAS, Eide PK, Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain: a journal of neurology 140, 2691– 2705 (2017). 28969373 PMC5841149 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sleep is needed to clear proteins from brain extracellular space; failure leads to aggregation, flow impedance, further fibril polymerization, and inflammation that suppresses glymphatic flow in affected regions.

    “We need sleep to clear proteins from the brain extracellular space, less they aggregate, impede flow, and in a vicious positive feedback cycle, potentiate further fibril polymerization, which together with inflammation then suppresses glymphatic flow in the most affected regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The most fundamental reason for sleep is self-preservation: only the sleeping brain can efficiently clear waste products generated during wakefulness.

    “Yet the most fundamental incentive for the brain to sleep lies in its own self-preservation: Only the sleeping brain is capable of efficiently cleaning up the waste products generated during active wakefulness.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    High incidence of interstitial lung disease in resolved COVID19 patients may predict higher risk of aggregation disorders, as greater risk of long-term heart failure may predict impaired lymphatic and glymphatic flow.

    “Indeed, the high incidence of interstitial lung disease that is emerging in patients with resolved COVID19 may predict a higher risk of aggregation disorders for these individuals going forward, as their greater risk of long-term heart failure may predict their impaired lymphatic and hence glymphatic flow.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Modulation of glymphatic flow and protein clearance requires deeper understanding of dependence of glymphatic and lymphatic flow on intracardiac pressures.

    “These systems are intimately connected, so that modulation of glymphatic flow and hence protein clearance from the brain will ultimately require a deeper understanding of the dependence of both glymphatic and lymphatic flow on intracardiac pressures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recent neuroimaging advances provide approaches to map the human glymphatic system and assess its functional competence in disease and effects on sleep-dependent glymphatic cyclicity.

    “In that regard, recent advances in neuroimaging have provided multiple approaches to map the human glymphatic system, and hence to assess its functional competence in the context of disease, as well as of the effects thereof on sleep-dependent glymphatic cyclicity (72, 73, 108).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [72] Terada T, In vivo direct relation of tau pathology with neuroinflammation in early Alzheimer’s disease. Journal of neurology 266, 2186– 2196 (2019). 31139959 source

      Not checked in the free run.

    • cites [73] Brundin P, Melki R, Kopito R, Prion-like transmission of protein aggregates in neurodegenerative diseases. Nature reviews. Molecular cell biology 11, 301– 307 (2010). 20308987 PMC2892479 source

      Not checked in the free run.

    • cites [108] Holth JK, The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363, 880– 884 (2019). 30679382 PMC6410369 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Diagnostic neuroimaging of glymphatic function via glymphograms may provide a means to predict risk of proteinopathies and evaluate efficacy of glymphatic flow-directed treatments.

    “The diagnostic neuroimaging of glymphatic function via such “glymphograms” may indeed provide both a means to predict the risk of developing proteinopathies, and an approach by which to evaluate the efficacy of glymphatic flow-directed treatments as they are developed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Amyloid-β, tau, and α-synuclein are present at higher levels in brain extracellular fluid and CSF during wakefulness than sleep; sleep deprivation increases their levels further.

    “amyloid-ß, tau and α-synuclein are all present at higher levels in the brain extracellular fluid and CSF during wakefulness than during sleep, and sleep deprivation increases their levels further (106–108).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [106] Bateman RJ, Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nature medicine 12, 856– 861 (2006). PMC2983090 16799555 source

      Not checked in the free run.

    • cites [107] Kang JE, Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005– 1007 (2009). 19779148 PMC2789838 source

      Not checked in the free run.

    • cites [108] Holth JK, The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363, 880– 884 (2019). 30679382 PMC6410369 source

      Not checked in the free run.

57 of 57

  • The paper relies on this without support.

    For brain homeostasis, protein clearance must approximately equal protein synthesis.

    “A fundamental tenet of brain homeostasis is that protein clearance must approximate protein synthesis.”

  • The paper relies on this without support.

    The ejection pressure of blood from the left ventricle is partly absorbed by the elastic arterial wall of the aorta.

    “To wit, the ejection pressure of blood from the left ventricle is partly absorbed by the elastic arterial wall of the aorta.”

  • The paper relies on this without support.

    Pulsatility in large caliber arteries transmits pressure waves along the axis of major vessels and through soft brain tissue.

    “Pulsatility in these large caliber arteries constantly transmits pressure waves along the axis of the major vessels, as well as through the soft brain tissue (Fig. 4).”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Insomnia may partially mediate depression risk for Alzheimer's and related dementias via beta-amyloid accumulation, tau protein aggregation, inflammation and blood-brain-barrier disruption.

    “Insomnia may partially mediate depression risk for Alzheimer's and related dementias via beta‐amyloid accumulation, tau protein aggregation, inflammation and blood‐brain‐barrier disruption204, 205, 206.”

    From Mental health care for older adults: recent advances and new directions in clinical practice and research (2022) · cites this paper as [206]

  • Data-driven proteomic analyses have revealed several biological pathways and molecular functions associated with cognitive impairment in late-life major depression, related to neuro-inflammatory control, neurotrophic support, cell survival/apoptosis, endothelial function, and lipid/protein metabolism.

    “Data‐driven proteomic analyses have revealed several biological pathways and molecular functions associated with cognitive impairment in late‐life major depression, related to neuro‐inflammatory control, neurotrophic support, cell survival/apoptosis, endothelial function, and lipid/protein metabolism204, 205, 206.”

    From Mental health care for older adults: recent advances and new directions in clinical practice and research (2022) · cites this paper as [206]

  • Several lines of evidence implicate meningeal-located structures in the genesis and progression of Alzheimer's disease (AD).

    “Several lines of evidence implicate meningeal-located structures in the genesis and progression of Alzheimer’s disease (AD)”

    From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Nedergaard and Goldman, 2020

  • The transport of interstitial fluids and macromolecules (including amyloid-β peptides) out of the brain occurs via a complex transport network that utilizes the perivascular glymphatic system of the brain and lymphatic vessels of the meninges.

    “The transport of interstitial fluids and macromolecules (including amyloid-β peptides) out of the brain occurs via a complex transport network that utilizes the perivascular glymphatic system of the brain and lymphatic vessels of the meninges”

    From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Nedergaard and Goldman, 2020

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Authors
Nedergaard, M., & Goldman, S. A.
Affiliations
University of Copenhagen (DK)
Corresponding author
  • Nedergaard, Maiken
  • Goldman, Steven A.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2020-10-02
Volume
370
Issue
6512
Pages
50-56
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.abb8739
PMC
PMC8186542
OpenAlex
W3089407290
Semantic Scholar
1581b29058a4261d11d32f29c0b5115b4594c81b
Cited by
1,145
References
116
Citations by year
2026: 293 · 2025: 272 · 2024: 161 · 2023: 165 · 2022: 138 · 2021: 114 · 2020: 2
FWCI
14.66
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Science (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • European Commission (HORIZON2020)
  • Lundbeckfonden (R155-2016-553, R155-2016–552)
  • Novo Nordisk
  • Novo Nordisk Fonden (NNF13OC0004258, NNF13OC0004260)
  • H. Lundbeck A/S
  • National Institute on Aging (RF1AG057575, RF1AG053991)
  • National Institute of Mental Health (R01MH104701)
  • National Institute of Neurological Disorders and Stroke (R01NS110776, RF1NS110049, R01NS100366)
  • H2020 European Research Council (742112)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
glymphatic system, dementia, sleep, sleep disorders, aging, neurodegenerative diseases, protein aggregation, brain waste clearance, sleep architecture, therapeutic target
MeSH terms
Prion Proteins, Glymphatic System, Aging, Alzheimer Disease, Animals, Cardiovascular Diseases, Humans, Lymphatic System, Polymorphism, Genetic, Sleep, Sleep Wake Disorders, Mice, Aquaporin 4, Protein Aggregates

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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