The DOI matches its Crossref record; 116 of the 116 references it cites were found in a registry or an index; 5 of the 146 sources its claims cite were checked for support.
Glymphatic failure as a final common pathway to dementia
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
86 Not checked yet · 20 Own interpretation · 3 Partly supported · 1 Supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The accumulation of low molecular weight CSF contrast agents (< 1 kDa) supports the notion that much larger proteins also get trapped in the tortuous extracellular spaces of deep brain regions.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Partly supportedcites [74] Ringstad G, Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI insight 3, (2018). PMC6124518 29997300 sourceExperimental — accuracy not yet measured
The Discussion (‘Tracer enrichment in deep brain structures’; page unavailable) reports contrast enhancement in deep white matter. It also says the MRI resolution could not resolve molecular motion in interstitial spaces. The paper does not establish that much larger proteins become trapped in tortuous extracellular spaces; it reports that the tracer declined after 24 hours and was cleared by four weeks. (LLM, conf=0.88)
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
The Discussion identifies gadobutrol as a low-molecular-weight CSF tracer (605 Da) and reports delayed clearance from CSF, while hypothesizing reduced clearance from brain tissue in idiopathic normal pressure hydrocephalus. It also links impaired glymphatic clearance to solutes such as amyloid-β. The paper does not establish that much larger proteins become trapped in tortuous extracellular spaces of deep brain regions. (LLM, conf=0.83)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“in which REM sleep disturbances often precede the onset of motor symptoms by several years, even decades (80, 81).”
§ Glymphatic failure as a final common pathway to dementia > Sleep, aging, neurodegeneration and the glymphatic system
What the sources say
- Not checked yetcites [80] Malhotra RK, Neurodegenerative Disorders and Sleep. Sleep medicine clinics 13, 63– 70 (2018). 29412984 source
- Partly supportedcites [81] Malkani R, Attarian H, Sleep in Neurodegenerative Disorders. Current sleep medicine reports 1, 81– 90 (2015). sourceExperimental — accuracy not yet measured
The “RBD as a Harbinger of Neurodegenerative Disease” section reports that REM sleep behavior disorder can precede a neurodegenerative diagnosis by several years, particularly Parkinson disease or dementia with Lewy bodies; it gives a median interval of 7.5 years. It does not establish that REM sleep disturbances often precede Parkinson motor symptoms by decades, and its finding concerns RBD specifically rather than REM sleep disturbances generally. Page numbers were not available in our copy. (LLM, conf=0.84)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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)”
§ Glymphatic failure as a final common pathway to dementia > Abstract
What the sources say
- Not checked yetcites [52] Kress BT, Impairment of paravascular clearance pathways in the aging brain. Annals of neurology 76, 845– 861 (2014). 25204284 PMC4245362 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Why do proteins aggregate in neurodegenerative diseases? · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias”
§ Glymphatic failure as a final common pathway to dementia > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“for which glymphatic failure may comprise a therapeutically targetable final common pathway”
§ Glymphatic failure as a final common pathway to dementia > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic-lymphatic system is a functionally integrated unit
What the sources say
- Not checked yetcites [39] Louveau A, Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337– 341 (2015). 26030524 PMC4506234 source
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“lymphatic vessels undergo atrophy in aging (48, 49)”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic-lymphatic system is a functionally integrated unit
What the sources say
- Not checked yetcites [48] Scallan JP, Zawieja SD, Castorena-Gonzalez JA, Davis MJ, Lymphatic pumping: mechanics, mechanisms and malfunction. The Journal of physiology 594, 5749– 5768 (2016). 27219461 PMC5063934 source
- Not checked yetcites [49] Jakic B, Kerjaschki D, Wick G, Lymphatic Capillaries in Aging. Gerontology, 1– 8 (2020). 32580201 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Accordingly, a large proportion of brain waste proteins and metabolites might then be expected to pass through, and be cleared, by the cervical lymphatics.”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic-lymphatic system is a functionally integrated unit
What the sources say
- Not checked yetcites [47] Pappolla M, Evidence for lymphatic Abeta clearance in Alzheimer’s transgenic mice. Neurobiology of disease 71, 215– 219 (2014). 25102344 PMC5589075 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Aging is also associated with a steep fall in glymphatic flow in the brains of both rodents and humans.”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [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 yetcites [52] Kress BT, Impairment of paravascular clearance pathways in the aging brain. Annals of neurology 76, 845– 861 (2014). 25204284 PMC4245362 source
- Not checked yetcites [53] Benveniste H, The Glymphatic System and Waste Clearance with Brain Aging: A Review. Gerontology 65, 106– 119 (2019). 29996134 PMC6329683 source
- Not checked yetcites [54] Zhou Y, Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human. Annals of neurology 87, 357– 369 (2020). 31916277 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“CSF inflow of larger tracers are reduced by up to 85% in aged wild-type mice”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [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 yetcites [52] Kress BT, Impairment of paravascular clearance pathways in the aging brain. Annals of neurology 76, 845– 861 (2014). 25204284 PMC4245362 source
- Not checked yetcites [53] Benveniste H, The Glymphatic System and Waste Clearance with Brain Aging: A Review. Gerontology 65, 106– 119 (2019). 29996134 PMC6329683 source
- Not checked yetcites [54] Zhou Y, Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human. Annals of neurology 87, 357– 369 (2020). 31916277 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Importantly, most of these age-related primary neurodegenerative diseases involve disorders of protein processing and aggregation.”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [59] Soto C, Unfolding the role of protein misfolding in neurodegenerative diseases. Nature reviews. Neuroscience 4, 49– 60 (2003). 12511861 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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None of the sources cited for this claim have been checked yet.
In the paper
“Infusion of amyloid-β into CSF acutely reduced glymphatic activity in wild-type mice suggesting a direct toxic effect (50, 55).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [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 yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“while contrast clearance in human brain tissue was inversely correlated to age in all subjects studied (50, 52–54).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [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 yetcites [52] Kress BT, Impairment of paravascular clearance pathways in the aging brain. Annals of neurology 76, 845– 861 (2014). 25204284 PMC4245362 source
- Not checked yetcites [53] Benveniste H, The Glymphatic System and Waste Clearance with Brain Aging: A Review. Gerontology 65, 106– 119 (2019). 29996134 PMC6329683 source
- Not checked yetcites [54] Zhou Y, Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human. Annals of neurology 87, 357– 369 (2020). 31916277 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“in human subjects, efflux of CSF containing amyloid-ß and phosphor-tau is reduced in patients with Alzheimer disease, compared to age-matched controls.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [70] de Leon MJ, Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. Journal of nuclear medicine: official publication, Society of Nuclear Medicine 58, 1471– 1476 (2017). PMC5577629 28302766 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Reduced glymphatic clearance might then be predicted to increase the risk of protein aggregation, given the combination of locally stagnant fluid flow together with the elevated extracellular concentration of the protein of interest.”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: For brain homeostasis, protein clearance must approximately equal protein synthesis.
In the paper
“Once a seed is formed, the aggregates attract monomers of the same protein, as well as other proteins which may be preferentially bound and entrapped (60).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“the suppression of glymphatic flow by deletion of AQP4 water channels sharply increased both amyloid-ß plaque formation and cognitive deficits in a mouse model of Alzheimer disease (69).”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [69] Xu Z, Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Abeta accumulation and memory deficits. Molecular neurodegeneration 10, 58 (2015). 26526066 PMC4631089 source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Proteins self-assemble and aggregate depending upon a number of factors, among which are structure, concentration, ionic strength and local pH, as well as their interactions with nucleating interfaces, such as phospholipid membranes (61, 62).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [61] Burke KA, Yates EA, Legleiter J, Biophysical insights into how surfaces, including lipid membranes, modulate protein aggregation related to neurodegeneration. Frontiers in neurology 4, 17 (2013). 23459674 PMC3585431 source
- Not checked yetcites [62] Yates EA, Specific domains of Abeta facilitate aggregation on and association with lipid bilayers. Journal of molecular biology 425, 1915– 1933 (2013). 23524134 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“The suppression of CSF in Alzheimer disease is so substantial that it can possible serve as a biomarker (70).”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [70] de Leon MJ, Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. Journal of nuclear medicine: official publication, Society of Nuclear Medicine 58, 1471– 1476 (2017). PMC5577629 28302766 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In the initial stages of AD, phosphorylated tau deposits in the entorhinal cortex, followed by the hippocampus and dorsal thalamus, while the neocortex becomes involved later.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [71] Hong S, Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712– 716 (2016). 27033548 PMC5094372 source
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In Parkinson’s disease and Lewy body disease, α-synuclein aggregates initially spread through the brainstem and olfactory bulb followed by limbic structures, and only thence to the neocortex.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [67] Jucker M, Walker LC, Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45– 51 (2013). 24005412 PMC3963807 source
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“The contrast agent remains trapped in the same regions for prolonged periods of time, especially if an underlying pathology is present (74, 75).”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [74] Ringstad G, Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI insight 3, (2018). PMC6124518 29997300 source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In each of these cases, the aggregates initially deposit at the ventral base of the forebrain and midbrain, and then extend rostrally and dorsally to the cortex.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [67] Jucker M, Walker LC, Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45– 51 (2013). 24005412 PMC3963807 source
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Yet the cognitive decline of Alzheimer disease correlates more closely with the later-occurring tauopathy and microglial activation, than with the earlier amyloid-ß plaque formation (71, 72).”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [71] Hong S, Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712– 716 (2016). 27033548 PMC5094372 source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In fact, the geographic pattern of macroscopic aggregate formation closely resembles that of entrapped CSF contrast agents during challenge of glymphatic flow in those brains (Fig. 3B).”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the geographic spread of aggregates in Alzheimer and Parkinson diseases clearly mirrors the pattern of glymphatic inflow in the human brain, as mapped by MRI.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, the regional variations in the path of seeding noted across the different types of neurodegenerative diseases may reflect region- and patient-specific variability in the rates of neuronal production of amyloid, tau, and α-synuclein.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
In the paper
“The most significant risk factor for developing protein aggregation – just as it is for developing dementia - is age (78).”
§ Glymphatic failure as a final common pathway to dementia > Sleep, aging, neurodegeneration and the glymphatic system
What the sources say
- Not checked yetcites [78] Hoyer S, Age as risk factor for sporadic dementia of the Alzheimer type? Annals of the New York Academy of Sciences 719, 248– 256 (1994). 8010597 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On that basis, we propose that trapping of aggregation-prone proteins in the extracellular space, rather that synaptic connectivity, is responsible for the patterns of protein spread in at least some proteinopathies.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Sampling of CSF and extracellular fluid have documented that amyloid-ß, tau and a-synuclein are all present outside the cytosol.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [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
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The age-related impairment in sleep quality may thus be causally involved in the increased incidence and accelerated course of neurodegenerative disease in the elderly, whose disrupted sleep architecture and depth may sharply diminish the clearance of brain fluid and its attendant export of protein waste, leading in turn to the stagnant interstitial flow that favors aggregate formation.”
§ Glymphatic failure as a final common pathway to dementia > Sleep, aging, neurodegeneration and the glymphatic system
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“the neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease, the multisystem atrophies, and the frontotemporal dementias, are all associated with sleep disturbances (80).”
§ Glymphatic failure as a final common pathway to dementia > Sleep, aging, neurodegeneration and the glymphatic system
What the sources say
- Not checked yetcites [80] Malhotra RK, Neurodegenerative Disorders and Sleep. Sleep medicine clinics 13, 63– 70 (2018). 29412984 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Yet AQP4 SNPs have also been associated with the rate of cognitive decline in longitudinally-followed cohorts of AD patients (84).”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“The polarized expression of the water channel, AQP4, in the vascular endfeet of astrocytes facilitates glymphatic fluid transport and amyloid-ß export in rodents (24, 30)(Fig. 1).”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
What the sources say
- Not checked yetcites [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 yetcites [30] Mestre H, Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7, (2018). PMC6307855 30561329 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“It has been known for decades that poor cardiovascular health negatively affects cognitive abilities (87, 88)”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [87] Knopman D, Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 56, 42– 48 (2001). 11148234 source
- Not checked yetcites [88] Leritz EC, McGlinchey RE, Kellison I, Rudolph JL, Milberg WP, Cardiovascular Disease Risk Factors and Cognition in the Elderly. Curr Cardiovasc Risk Rep 5, 407– 412 (2011). 22199992 PMC3245189 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Indeed, a recent study reported that deletion of AQP4 accelerated amyloid plaque formation in a murine model of Alzheimer disease (69).”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
What the sources say
- Not checked yetcites [69] Xu Z, Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Abeta accumulation and memory deficits. Molecular neurodegeneration 10, 58 (2015). 26526066 PMC4631089 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Similarly, the expression of a cluster of transcripts encoding proteins associated with astrocytic end-feet predicted lower levels of cortical phospho-tau in human subjects (86).”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
What the sources say
- Not checked yetcites [86] Simon MJ, Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology. Scientific reports 8, 12389 (2018). 30120299 PMC6098119 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The study demonstrating that a common single nucleotide polymorphism (SNP) of AQP4 was linked to changes in slow wave activity during NREM sleep, that were mirrored by changes in daytime sleepiness as well as in altered reaction times during extended wakefulness (83).”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
What the sources say
- Not checked yetcites [83] Ulv Larsen SM, Haplotype of the astrocytic water channel AQP4 is associated with slow wave energy regulation in human NREM sleep. PLoS biology 18, e3000623 (2020). 32369477 PMC7199924 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“SVD is linked glymphatic dysfunction in experimental models (91)”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [91] Mortensen KN, Impaired Glymphatic Transport in Spontaneously Hypertensive Rats. The Journal of neuroscience: the official journal of the Society for Neuroscience 39, 6365– 6377 (2019). 31209176 PMC6687896 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The motion of the brain is locally supplemented by the pulsatility of the penetrating arteries, as they enter the brain from the CSF-filled subarachnoid space, thereby driving CSF into the neuropil along the periarteral spaces (24).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The stiffening of perivascular glycocalyx of diabetic patients accomplishes much the same (101)”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [101] Jiang Q, Impairment of the glymphatic system after diabetes. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 37, 1326– 1337 (2017). PMC5453454 27306755 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“It has been shown that glymphatic function is suppressed in hypertensive rats (91, 92).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [91] Mortensen KN, Impaired Glymphatic Transport in Spontaneously Hypertensive Rats. The Journal of neuroscience: the official journal of the Society for Neuroscience 39, 6365– 6377 (2019). 31209176 PMC6687896 source
- Not checked yetcites [92] Xue Y, Concomitant enlargement of perivascular spaces and decrease in glymphatic transport in an animal model of cerebral small vessel disease. Brain research bulletin 161, 78– 83 (2020). 32353396 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“As the ejected blood transits the arteries, it enlarges the arterial diameter as its pulse wave propagates downstream (28).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [28] Mestre H, Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nature communications 9, 4878 (2018). PMC6242982 30451853 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We also propose that a healthy cardiovascular system, besides its role in delivering energy metabolites to the brain, plays a hitherto-unappreciated role in the clearance of neurotoxic wastes from the brain.”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In particular, we have found that the brain’s fluid transport system is designed to take advantage of cardiac pulsatility to drive CSF transport in the neuropil (28).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [28] Mestre H, Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nature communications 9, 4878 (2018). PMC6242982 30451853 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The ejection pressure of blood from the left ventricle is partly absorbed by the elastic arterial wall of the aorta.
- Rests on an assumption: Pulsatility in large caliber arteries transmits pressure waves along the axis of major vessels and through soft brain tissue.
In the paper
“It should not be surprising that heart disease associated with reduced cardiac output, including such common entities as congestive heart failure and atrial dysrhythmias (95), are associated with diminished glymphatic flow, since the pulsatility of the cerebral arteries and hence the driving forces within the glymphatic system arereduced.”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [95] Vogels RL, Profile of cognitive impairment in chronic heart failure. Journal of the American Geriatrics Society 55, 1764– 1770 (2007). 17727641 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The ejection pressure of blood from the left ventricle is partly absorbed by the elastic arterial wall of the aorta.
- Rests on an assumption: Pulsatility in large caliber arteries transmits pressure waves along the axis of major vessels and through soft brain tissue.
In the paper
“Indeed, PET imaging showed that a single night of sleep deprivation resulted in a significant increase in Amyloid-β burden in the hippocampus and thalamus (109).”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
What the sources say
- Not checked yetcites [109] Shokri-Kojori E, beta-Amyloid accumulation in the human brain after one night of sleep deprivation. Proceedings of the National Academy of Sciences of the United States of America 115, 4483– 4488 (2018). 29632177 PMC5924922 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“It is no wonder then that the clinical distinctions between Alzheimer’s and the vascular dementias often is blurred by their frequent co-association (102).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [102] Sweeney MD, Vascular dysfunction-The disregarded partner of Alzheimer’s disease. Alzheimer’s & dementia: the journal of the Alzheimer’s Association 15, 158– 167 (2019). PMC6338083 30642436 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The neurodegenerative dementias may thus be viewed as the products of a final common pathway that integrates the dysfunction of any and all of these closely interdependent upstream mechanisms (Fig. 3B).”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these observations suggest a causal linkage between the sleep-wake cycle and its regulation of fluid flow via the glymphatics, and the modulation thereby of the balance between protein clearance and aggregation.”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, they suggest a basis for the increased incidence of aggregation-related disorders seen with aging, the appearance of which tracks age-related declines in both vascular health and glymphatic patency.”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“SVD is linked glymphatic dysfunction in experimental models (91), and may potentiate the progression of neurodegenerative dementias in precisely the same patients at risk for SVD-associated vascular dementia.”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [91] Mortensen KN, Impaired Glymphatic Transport in Spontaneously Hypertensive Rats. The Journal of neuroscience: the official journal of the Society for Neuroscience 39, 6365– 6377 (2019). 31209176 PMC6687896 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 52
- Probably not a substantial claim. 12
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
What the sources say
- Supportedcites [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
The Results section (‘AQP4 SNPs and cognitive and functional decline’) reports that, after AD diagnosis, rs9951307 and rs3875089 were associated with slower cognitive decline, while rs3763040 and rs3763043 were associated with more rapid decline. This matches the two pairs of SNPs and the direction of decline attributed to the paper. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
The Introduction links impaired glymphatic transport to waste accumulation and several neurological conditions. The Discussion section on brain enhancement and gadobutrol clearance hypothesizes a shared pathogenic mechanism for iNPH dementia and Alzheimer’s disease. Neither passage proposes directed regulation of the glymphatic system as a disease-modifying treatment, so the therapeutic-opportunity part is unsupported. (LLM, conf=0.82)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
- Partly supported
None of the sources cited for this claim have been checked yet.
In the paper
“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)”
§ Glymphatic failure as a final common pathway to dementia > Abstract
What the sources say
- Not checked yetcites [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 yetcites [80] Malhotra RK, Neurodegenerative Disorders and Sleep. Sleep medicine clinics 13, 63– 70 (2018). 29412984 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Sleep, aging, neurodegeneration and the glymphatic system · plain
In the paper
“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”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: For brain homeostasis, protein clearance must approximately equal protein synthesis.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Glymphatic failure as a final common pathway to dementia > Abstract
What the sources say
- Not checked yetcites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: For brain homeostasis, protein clearance must approximately equal protein synthesis.
- Also stated in: § The glymphatic and lymphatic systems · plain
In the paper
“the antecedent sleep loss can be identified post hoc by an increase in EEG slow wave activity during recovery sleep (8)”
§ Glymphatic failure as a final common pathway to dementia > Why do we sleep?
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“glymphatic clearance is temporally regulated and cyclically so, in that fluid transport is enabled by sleep and suppressed during wakefulness.”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“As such, waste removal is likely most efficient in the early hours of sleep, and especially during recovery sleep after prolonged wakefulness (37).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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),”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [38] Hablitz L, Circadian control of brain glymphatic/lymphatic fluid flow. Nature communications (in press), (2020). PMC7468152 32879313 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [29] Nagelhus EA, Ottersen OP, Physiological roles of aquaporin-4 in brain. Physiological reviews 93, 1543– 1562 (2013). 24137016 PMC3858210 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Deletion of AQP4 channels reduces both the influx of CSF tracers and the efflux of solutes from the neuropil (24, 30, 31).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [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 yetcites [30] Mestre H, Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7, (2018). PMC6307855 30561329 source
- Not checked yetcites [31] Mestre H, Cerebrospinal fluid influx drives acute ischemic tissue swelling. Science 367, (2020). PMC7375109 32001524 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [34] Mestre H, Mori Y, Nedergaard M, The Brain’s Glymphatic System: Current Controversies. Trends in neurosciences, (2020). PMC7331945 32423764 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Brain fluid transport initiates and proceeds during NREM sleep, and CSF tracer influx correlates with the prevalence of EEG slow wave activity (35, 36).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic and lymphatic systems
What the sources say
- Not checked yetcites [38] Hablitz L, Circadian control of brain glymphatic/lymphatic fluid flow. Nature communications (in press), (2020). PMC7468152 32879313 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic-lymphatic system is a functionally integrated unit
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“VEGFC-overexpression induced spouting of the meningeal lymphatic vessels and slowed the cognitive decline in a mouse model of Alzheimer disease (50).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic-lymphatic system is a functionally integrated unit
What the sources say
- Not checked yetcites [50] Da Mesquita S, Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185– 191 (2018). 30046111 PMC6085146 source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic-lymphatic system is a functionally integrated unit
What the sources say
- Not checked yetcites [39] Louveau A, Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337– 341 (2015). 26030524 PMC4506234 source
- Not checked yetcites [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 yetcites [42] Ahn JH, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62– 66 (2019). 31341278 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic-lymphatic system is a functionally integrated unit
What the sources say
- Not checked yetcites [47] Pappolla M, Evidence for lymphatic Abeta clearance in Alzheimer’s transgenic mice. Neurobiology of disease 71, 215– 219 (2014). 25102344 PMC5589075 source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > The glymphatic-lymphatic system is a functionally integrated unit
What the sources say
- Not checked yetcites [42] Ahn JH, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62– 66 (2019). 31341278 source
- Not checked yetcites [43] Ma Q, Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain. Acta neuropathologica 137, 151– 165 (2019). 30306266 PMC6338719 source
- Not checked yetcites [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 yetcites [45] Jacob L, Anatomy and function of the vertebral column lymphatic network in mice. Nature communications 10, 4594 (2019). PMC6785564 31597914 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [52] Kress BT, Impairment of paravascular clearance pathways in the aging brain. Annals of neurology 76, 845– 861 (2014). 25204284 PMC4245362 source
- Not checked yetcites [42] Ahn JH, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62– 66 (2019). 31341278 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The hallmark feature of these proteinopathies are the fibrillary aggregates of misfolded or hyperphosphorylated proteins (59).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [59] Soto C, Unfolding the role of protein misfolding in neurodegenerative diseases. Nature reviews. Neuroscience 4, 49– 60 (2003). 12511861 source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The recent discovery that specific misfolded and aggregated proteins can propagate and spread in a prion-like fashion has sparked considerable interest (67).”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [67] Jucker M, Walker LC, Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45– 51 (2013). 24005412 PMC3963807 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. It may state two separate claims as one.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Why do proteins aggregate in neurodegenerative diseases?
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plainconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“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”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [74] Ringstad G, Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI insight 3, (2018). PMC6124518 29997300 source
- Not checked yetcites [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
boosted- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [71] Hong S, Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712– 716 (2016). 27033548 PMC5094372 source
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“These proteins all lack N-terminal signal sequences, so that unconventional mechanisms must be responsible for their release (76).”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Sleep, aging, neurodegeneration and the glymphatic system
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“several studies have highlighted the critical role of oligomers as both directly toxic, and as niduses for macromolecular aggregation.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“while proteins involved in neurodegenerative diseases may normally be either intracellular or extracellular in nature, all are present in the extracellular space.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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)”
§ Glymphatic failure as a final common pathway to dementia > Sleep, aging, neurodegeneration and the glymphatic system
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“sleep quality decreases as a function of normal aging. Insomnia is more frequent with age, and total sleep duration becomes shorter and more interrupted.”
§ Glymphatic failure as a final common pathway to dementia > Sleep, aging, neurodegeneration and the glymphatic system
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > Spread of protein aggregates: A possible role of the glymphatic system?
What the sources say
- Not checked yetcites [77] Knopman DS, Sifting through a failed Alzheimer trial: What biomarkers tell us about what happened. Neurology 90, 447– 448 (2018). 29429973 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“while cardiovascular fitness positively correlates with cognition in young adults (89) and preserves cognitive performance with aging (90).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In man, genetic variation in AQP4 has been shown to impact both sleep and amyloid-β burden (82).”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: For brain homeostasis, protein clearance must approximately equal protein synthesis.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > AQP4 polymorphisms in sleep and neurodegeneration
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [95] Vogels RL, Profile of cognitive impairment in chronic heart failure. Journal of the American Geriatrics Society 55, 1764– 1770 (2007). 17727641 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [96] Wardlaw JM, Smith C, Dichgans M, Small vessel disease: mechanisms and clinical implications. The Lancet. Neurology 18, 684– 696 (2019). 31097385 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [97] Iadecola C, The pathobiology of vascular dementia. Neuron 80, 844– 866 (2013). 24267647 PMC3842016 source
- Not checked yetcites [98] Zlokovic BV, Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nature reviews. Neuroscience 12, 723– 738 (2011). 22048062 PMC4036520 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Glymphatic failure links cardiovascular with neurodegenerative disease
What the sources say
- Not checked yetcites [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 yetcites [100] Wardlaw JM, Perivascular spaces in the brain: anatomy, physiology and pathology. Nature reviews. Neurology 16, 137– 153 (2020). 32094487 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Glymphatic failure as a final common pathway to dementia > Conclusion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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).”
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?
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
Citations
Cites
Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., Benveniste, H., Vates, G. E., Deane, R., Goldman, S. A., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003748 · Cited by 5,824
Self-citationSleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411
Self-citationStructural and functional features of central nervous system lymphatic vessels
Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., et al. (2015) · Nature · doi:10.1038/nature14432 · Cited by 4,413
Two-Process Model of Sleep Regulation
Binder, M. D., Hirokawa, N., & Windhorst, U. (2008) · Springer eBooks · doi:10.1007/978-3-540-29678-2_6166 · Cited by 3,900
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343
Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders
Zlokovic, B. V. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3114 · Cited by 2,969
Regularly Occurring Periods of Eye Motility, and Concomitant Phenomena, During Sleep
Aserinsky, E., & Kleitman, N. (1953) · Science · doi:10.1126/science.118.3062.273 · Cited by 2,488
Tononi, G., & Cirelli, C. (2014) · Neuron · doi:10.1016/j.neuron.2013.12.025 · Cited by 2,356
The blood–brain barrier: an overview
Ballabh, P., Braun, A., & Nedergaard, M. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.12.016 · Cited by 2,276
Self-citationA dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
Aspelund, A., Antila, S., Proulx, S. T., Karlsen, T. V., Karaman, S., Detmar, M., Wiig, H., & Alitalo, K. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142290 · Cited by 2,198
Cited by
Sorted by citations
Rasmussen, M. K., Mestre, H., & Nedergaard, M. (2021) · Physiological Reviews · doi:10.1152/physrev.00031.2020 · Cited by 642
Self-citationNeuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638
“Arterial pulsations drive CSF from peri-arterial to intraparenchymal spaces, and this CSF is then reabsorbed at the peri-venule spaces with the aid of the glial AQP4 molecule 422,423 .”
The Glymphatic System: A Novel Component of Fundamental Neurobiology
Hablitz, L. M., & Nedergaard, M. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.0619-21.2021 · Cited by 503
“…with their implications for neuropathology, have been reviewed at length in the recent literature (Kent and Mistlberger, 2017; Abbott et al., 2018; Rasmussen et al., 2018; Sun et al., 2018; Thomas, 2019; Nedergaard and Goldman, 2020; Troili et al., 2020; Wardlaw et al., 2020; Mestre et al., 2020a).”
BackgroundSelf-citationReynolds, C. F., Jeste, D. V., Sachdev, P. S., & Blazer, D. G. (2022) · World Psychiatry · doi:10.1002/wps.20996 · Cited by 465
Mou, Y., Du, Y., Zhou, L., Yue, J., Hu, X., Liu, Y., Chen, S., Lin, X., Zhang, G., Xiao, H., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.796288 · Cited by 432
“The concept of glymphatic innovates a previous conjecture that brain homeostasis depends on the classical cellular protein degradation pathway to maintain the protein balance between synthesis and clearance (55).”
Background
Metadata
- Authors
- Nedergaard, M., & Goldman, S. A.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Nedergaard, Maiken
- Goldman, Steven A.
- Venue
- Science
- Published
- 2020-10-02
- Volume
- 370
- Issue
- 6512
- Pages
- 50-56
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
About these checks
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.
A language model drew the claims from the paper on 2026-10-05, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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