Amyloid-β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle
Open accessAbstract
Sleep and Alzheimer's Disease: Accumulation of amyloid-β (Aβ) in the brain is thought to be the initiating event in the pathogenesis of Alzheimer's disease (AD). Aβ is a peptide secreted in a soluble monomeric form predominantly by neurons and its aggregation into toxic forms is concentration dependent. Synaptic activity regulates the release of Aβ in vivo. However, how physiological and environmental processes are involved in regulation of Aβ levels is not understood. Kang et al. (p. 1005 , published online 24 September), by performing sleep-wake studies in freely behaving animals concomitant with in vivo microdialysis, found that brain interstitial fluid levels of Aβ were significantly correlated with wakefulness and negatively correlated with sleep. Furthermore, relatively short-term (3 weeks) sleep deprivation markedly accelerated amyloid plaque deposition in amyloid precursor protein transgenic mice. Thus, sleep-wake behavior is linked to Aβ levels and abnormal sleep may be linked to AD pathogenesis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
The extracted pools measured do not completely reflect the ISF pool of Aβ.
“perhaps suggesting the extracted pools we measured do not completely reflect the ISF pool of Aβ (31, 38).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [38]
Amyloid-β, tau, and α-synuclein are present at higher levels in brain extracellular fluid and CSF during wakefulness than sleep; sleep deprivation increases their levels further.
“amyloid-ß, tau and α-synuclein are all present at higher levels in the brain extracellular fluid and CSF during wakefulness than during sleep, and sleep deprivation increases their levels further (106–108).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [107]
In mice, interstitial fluid Aβ levels correlate with wakefulness and increase after acute sleep deprivation or orexin infusion.
“In animal microdialysis experiments, interstitial fluid (ISF) Aβ levels correlate with wakefulness and significantly increase following acute sleep deprivation or orexin infusion.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Kang et al., 2009
Chronic orexin receptor blockade that increases sleep decreases amyloid plaque deposition.
“A decrease in amyloid plaque deposition was observed after chronic orexin receptor blockade resulting in increased sleep (Kang et al., 2009).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Kang et al., 2009
Acute sleep deprivation increases amyloid plaque deposition in Aβ-overexpressing mice.
“In mice overexpressing Aβ, acute sleep deprivation caused a significant increase in amyloid plaque deposition.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Kang et al., 2009
APP and Aβ homeostasis are exquisitely regulated processes, and bioenergetic metabolism regulates these processes.
“Overall, we feel we can confidently state APP and Aβ homeostasis are exquisitely regulated processes, and bioenergetic metabolism regulates these processes.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [178]
Abundant data from human and cell-based studies either suggest or demonstrate bioenergetic factors regulate both APP processing and Aβ production.
“Whether Aβ changes precede either age-related or AD-related brain bioenergetic changes is less clear-cut, especially since abundant data from human and cell-based studies either suggest or demonstrate bioenergetic factors regulate both APP processing and Aβ production [95–100].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [100]
Whether Aβ changes precede either age-related or AD-related brain bioenergetic changes is less clear-cut.
“Whether Aβ changes precede either age-related or AD-related brain bioenergetic changes is less clear-cut, especially since abundant data from human and cell-based studies either suggest or demonstrate bioenergetic factors regulate both APP processing and Aβ production [95–100].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [100]
Soluble Aβ levels vary throughout the day, rising during wakefulness and falling during sleep.
“Soluble Aβ levels also vary throughout the day, rising during wakefulness and falling during sleep [100].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [100]
Bioenergetic metabolism affects APP processing and Aβ production.
“Bioenergetic metabolism certainly affects APP processing and Aβ production.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [100]
Extracellular occurrence of oligomers is consistent with the rapid outpouring of Aβ, and perhaps small oligomers, into brain interstitial fluid, measured by microdialysis in mouse models and humans.
“Extracellular occurrence of oligomers is consistent with the rapid outpouring of Aβ, and perhaps small oligomers, into brain interstitial fluid, measured by microdialysis in mouse models and humans (Cirrito et al., 2005; Kang et al., 2007; Kang et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Kang et al., 2009
Sleep deprivation increases interstitial fluid levels of amyloid-β and increases plaque formation in mice and flies, whereas in Drosophila, genetically increasing sleep reduces amyloid-β deposition.
“Sleep deprivation increases interstitial fluid levels of Aβ and increases plaque formation in mice and flies287,288, whereas in Drosophila, genetically increasing sleep reduces Aβ deposition288.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [287]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210 · see citing works
Neurons containing hypocretin (orexin) project to multiple neuronal systems
Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., & Kilduff, T. S. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09996.1998 · Cited by 3,466 · see citing works
APP Processing and Synaptic Function
Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S., & Malinow, R. (2003) · Neuron · doi:10.1016/s0896-6273(03)00124-7 · Cited by 1,644 · see citing works
Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo
Cirrito, J. R., Yamada, K. A., Finn, M. B., Sloviter, R. S., Bales, K. R., May, P. C., Schoepp, D. D., Paul, S. M., Mennerick, S., & Holtzman, D. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.10.028 · Cited by 1,265 · see citing works
Self-citationCell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases
Selkoe, D. J. (2004) · Nature Cell Biology · doi:10.1038/ncb1104-1054 · Cited by 863 · see citing works
Vyazovskiy, V. V., Cirelli, C., Pfister-Genskow, M., Faraguna, U., & Tononi, G. (2008) · Nature Neuroscience · doi:10.1038/nn2035 · Cited by 837 · see citing works
Arousal effect of orexin A depends on activation of the histaminergic system
Huang, Z., Qu, W., Li, W., Mochizuki, T., Eguchi, N., Watanabe, T., Urade, Y., & Hayaishi, O. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181330998 · Cited by 555 · see citing works
Yoshida, Y., Fujiki, N., Nakajima, T., Ripley, B. A., Matsumura, H., Yoneda, H., Mignot, E. J.-M., & Nishino, S. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01725.x · Cited by 449 · see citing works
Self-citationWidespread Changes in Synaptic Markers as a Function of Sleep and Wakefulness in <i>Drosophila</i>
Gilestro, G. F., Tononi, G., & Cirelli, C. (2009) · Science · doi:10.1126/science.1166673 · Cited by 360 · see citing works
Characterizing the Appearance and Growth of Amyloid Plaques in APP/PS1 Mice
Yan, P., Bero, A. W., Cirrito, J. R., Xiao, Q., Hu, X., Wang, Y., Gonzales, E., Holtzman, D. M., & Lee, J.-M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2637-09.2009 · Cited by 264 · see citing works
Self-citationUse-Dependent Plasticity in Clock Neurons Regulates Sleep Need in Drosophila
Donlea, J. M., Ramanan, N., & Shaw, P. J. (2009) · Science · doi:10.1126/science.1166657 · Cited by 251 · see citing works
Kang, J.-E., Cirrito, J. R., Dong, H., Csernansky, J. G., & Holtzman, D. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700148104 · Cited by 219 · see citing works
Neurobiology of Sleep Disturbances in Neurodegenerative Disorders
Gagnon, J., Petit, D., Latreille, V., & Montplaisir, J. Y. (2008) · Current Pharmaceutical Design · doi:10.2174/138161208786549353 · Cited by 65 · see citing works
New Developments in Sleep Research: Molecular Genetics, Gene Expression, and Systems Neurobiology
Kilduff, T. S., Lein, E. S., de la Iglesia, H. O., Sakurai, T., Fu, Y., & Shaw, P. J. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3768-08.2008 · Cited by 26 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sleep 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 · see citing works
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
Self-citationKnopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00269-y · Cited by 2,606 · see citing works
Self-citationHippocampal sharp wave-ripple: A cognitive biomarker for episodic memory and planning
Buzsáki, G. (2015) · Hippocampus · doi:10.1002/hipo.22488 · Cited by 1,759 · see citing works
Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks
Palop, J. J., & Mucke, L. (2010) · Nature Neuroscience · doi:10.1038/nn.2583 · Cited by 1,651 · see citing works
The Sleep-Immune Crosstalk in Health and Disease
Besedovsky, L., Lange, T., & Haack, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00010.2018 · Cited by 1,479 · see citing works
Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep
Fultz, N. E., Bonmassar, G., Setsompop, K., Stickgold, R. A., Rosen, B. R., Polimeni, J. R., & Lewis, L. D. (2019) · Science · doi:10.1126/science.aax5440 · Cited by 1,197 · see citing works
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · see citing works
Self-citationGlymphatic failure as a final common pathway to dementia
Nedergaard, M., & Goldman, S. A. (2020) · Science · doi:10.1126/science.abb8739 · Cited by 1,145 · see citing works
Yaffe, K., Laffan, A. M., Harrison, S. L., Redline, S., Spira, A. P., Ensrud, K. E., Ancoli-Israel, S., & Stone, K. L. (2011) · JAMA · doi:10.1001/jama.2011.1115 · Cited by 1,137 · see citing works
Sleep and Alzheimer disease pathology--a bidirectional relationship
Ju, Y.-E. S., Lucey, B. P., & Holtzman, D. M. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.269 · Cited by 996 · see citing works
Self-citationNetwork abnormalities and interneuron dysfunction in Alzheimer disease
Palop, J. J., & Mucke, L. (2016) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.141 · Cited by 1,022 · see citing works
Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction
Mucke, L., & Selkoe, D. J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006338 · Cited by 1,000 · see citing works
Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways
Greenberg, S. M., Bacskai, B. J., Hernandez-Guillamon, M., Pruzin, J., Sperling, R., & van Veluw, S. J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-019-0281-2 · Cited by 947 · see citing works
Mechanisms linking circadian clocks, sleep, and neurodegeneration
Musiek, E. S., & Holtzman, D. M. (2016) · Science · doi:10.1126/science.aah4968 · Cited by 878 · see citing works
Self-citationβ-Amyloid accumulation in the human brain after one night of sleep deprivation
Shokri-Kojori, E., Wang, G.-J., Wiers, C. E., Demiral, S. B., Guo, M., Kim, S. W., Lindgren, E., Ramirez, V., Zehra, A., Freeman, C., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1721694115 · Cited by 893 · see citing works
Neuronal activity regulates the regional vulnerability to amyloid-β deposition
Bero, A. W., Yan, P., Roh, J. H., Cirrito, J. R., Stewart, F. R., Raichle, M. E., Lee, J.-M., & Holtzman, D. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2801 · Cited by 880 · see citing works
Self-citationLim, A. S. P., Kowgier, M., Yu, L., Buchman, A. S., & Bennett, D. A. (2013) · Sleep · doi:10.5665/sleep.2802 · Cited by 793 · see citing works
The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans
Holth, J. K., Fritschi, S. K., Wang, C., Pedersen, N. P., Cirrito, J. R., Mahan, T. E., Finn, M. B., Manis, M., Geerling, J. C., Fuller, P. M., et al. (2019) · Science · doi:10.1126/science.aav2546 · Cited by 813 · see citing works
Self-citationConnections between sleep and cognition in older adults
Yaffe, K., Falvey, C. M., & Hoang, T. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70172-3 · Cited by 796 · see citing works
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786 · see citing works
Sleep Quality and Preclinical Alzheimer Disease
Ju, Y.-E. S., McLeland, J. S., Toedebusch, C. D., Xiong, C., Fagan, A. M., Duntley, S. P., Morris, J. C., & Holtzman, D. M. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.2334 · Cited by 744 · see citing works
Self-citationRhythms of life: circadian disruption and brain disorders across the lifespan
Logan, R. W., & McClung, C. A. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0088-y · Cited by 713 · see citing works
Memory loss in Alzheimer's disease
Jahn, H. (2013) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2013.15.4/hjahn · Cited by 653 · see citing works
Protein transmission in neurodegenerative disease
Peng, C., Trojanowski, J. Q., & Lee, V. M.-Y. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0333-7 · Cited by 625 · see citing works
The Brain’s Glymphatic System: Current Controversies
Mestre, H., Mori, Y., & Nedergaard, M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.04.003 · Cited by 609 · see citing works
Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels
Ju, Y.-E. S., Ooms, S. J., Sutphen, C., Macauley, S. L., Zangrilli, M. A., Jerome, G., Fagan, A. M., Mignot, E., Zempel, J. M., Claassen, J. A. H. R., et al. (2017) · Brain · doi:10.1093/brain/awx148 · Cited by 604 · see citing works
Self-citationRoh, J. H., Huang, Y., Bero, A. W., Kasten, T., Stewart, F. R., Bateman, R. J., & Holtzman, D. M. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004291 · Cited by 563 · see citing works
Self-citationThe Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100339 · Cited by 562 · see citing works
“Interstitial fluid Aβ levels also vary with sleepwake cycles; in mice, wakefulness associates with increased interstitial fluid Aβ, and sleep associates with decreased interstitial fluid Aβ [85].”
BackgroundSleep, circadian rhythms, and the pathogenesis of Alzheimer disease
Musiek, E. S., Xiong, D. D., & Holtzman, D. M. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.121 · Cited by 529 · see citing works
Self-citationTranah, G. J., Blackwell, T., Stone, K. L., Ancoli‐Israel, S., Paudel, M. L., Ensrud, K. E., Cauley, J. A., Redline, S., Hillier, T. A., Cummings, S. R., et al. (2011) · Annals of Neurology · doi:10.1002/ana.22468 · Cited by 525 · see citing works
Circadian rest-activity pattern changes in aging and preclinical Alzheimer disease
Musiek, E. S., Bhimasani, M., Zangrilli, M. A., Morris, J. C., Holtzman, D. M., & Ju, Y.-E. S. (2018) · JAMA Neurology · doi:10.1001/jamaneurol.2017.4719 · Cited by 465 · see citing works
Self-citationSleep function: Toward elucidating an enigma
Krueger, J. M., Frank, M. G., Wisor, J. P., & Roy, S. (2016) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2015.08.005 · Cited by 440 · see citing works
Synapses and Alzheimer's Disease
Sheng, M., Sabatini, B. L., & Sudhof, T. C. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005777 · Cited by 436 · see citing works
Ooms, S., Overeem, S., Besse, K., Rikkert, M. O., Verbeek, M., & Claassen, J. A. H. R. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.1173 · Cited by 438 · see citing works
The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease
Ferreira, S. T., & Klein, W. L. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.003 · Cited by 442 · see citing works
Neuropsychiatric signs and symptoms of Alzheimer's disease: New treatment paradigms
Lanctôt, K. L., Amatniek, J., Ancoli‐Israel, S., Arnold, S. E., Ballard, C., Cohen‐Mansfield, J., Ismail, Z., Lyketsos, C., Miller, D. S., Musiek, E., et al. (2017) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.07.001 · Cited by 395 · see citing works
Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics
Lucey, B. P., Hicks, T. J., McLeland, J. S., Toedebusch, C. D., Boyd, J., Elbert, D. L., Patterson, B. W., Baty, J., Morris, J. C., Ovod, V., et al. (2018) · Annals of Neurology · doi:10.1002/ana.25117 · Cited by 362 · see citing works
Self-citationCircadian Rhythms, Sleep, and Disorders of Aging
Mattis, J., & Sehgal, A. (2016) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.02.003 · Cited by 369 · see citing works
Synapse Pathology in Psychiatric and Neurologic Disease
van Spronsen, M., & Hoogenraad, C. C. (2010) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-010-0104-8 · Cited by 345 · see citing works
Hu, Y., Shmygelska, A., Tran, D., Eriksson, N., Tung, J. Y., & Hinds, D. A. (2016) · Nature Communications · doi:10.1038/ncomms10448 · Cited by 321 · see citing works
Brain aging, Alzheimer's disease, and mitochondria
Swerdlow, R. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.012 · Cited by 306 · see citing works
“Whether Aβ changes precede either age-related or AD-related brain bioenergetic changes is less clear-cut, especially since abundant data from human and cell-based studies either suggest or demonstrate bioenergetic factors regulate both APP processing and Aβ production [95–100].”
BackgroundAging and Alzheimer's disease: comparison and associations from molecular to system level
Xia, X., Jiang, Q., McDermott, J., & Han, J. J. (2018) · Aging Cell · doi:10.1111/acel.12802 · Cited by 301 · see citing works
Zempel, H., Luedtke, J., Kumar, Y., Biernat, J., Dawson, H., Mandelkow, E., & Mandelkow, E. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.207 · Cited by 283 · see citing works
Deciphering the astrocyte reaction in Alzheimer's disease
Perez-Nievas, B. G., & Serrano-Pozo, A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00114 · Cited by 282 · see citing works
The gut microbiome in Alzheimer’s disease: what we know and what remains to be explored
Chandra, S., Sisodia, S. S., & Vassar, R. J. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00595-7 · Cited by 278 · see citing works
Snyder, H. M., Asthana, S., Bain, L., Brinton, R., Craft, S., Dubal, D. B., Espeland, M. A., Gatz, M., Mielke, M. M., Raber, J., et al. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.08.004 · Cited by 262 · see citing works
Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET
de Leon, M. J., Li, Y., Okamura, N., Tsui, W. H., Saint-Louis, L. A., Glodzik, L., Osorio, R. S., Fortea, J., Butler, T., Pirraglia, E., et al. (2017) · Journal of Nuclear Medicine · doi:10.2967/jnumed.116.187211 · Cited by 246 · see citing works
Genetic basis of chronotype in humans: insights from three landmark GWAS
Kalmbach, D. A., Schneider, L. D., Cheung, J., Bertrand, S. J., Kariharan, T., Pack, A. I., & Gehrman, P. R. (2017) · Sleep · doi:10.1093/sleep/zsw048 · Cited by 243 · see citing works
An ocular glymphatic clearance system removes β-amyloid from the rodent eye
Wang, X., Lou, N., Eberhardt, A., Yang, Y., Kusk, P., Xu, Q., Förstera, B., Peng, S., Shi, M., Ladrón-de-Guevara, A., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw3210 · Cited by 239 · see citing works
Meléndez-Fernández, O. H., Liu, J. A., & Nelson, R. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043392 · Cited by 227 · see citing works
Lifespan brain activity, β-amyloid, and Alzheimer's disease
Jagust, W. J., & Mormino, E. C. (2011) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2011.09.004 · Cited by 221 · see citing works
The Relationship between Obstructive Sleep Apnea and Alzheimer’s Disease
Andrade, A. G., Bubu, O. M., Varga, A. W., & Osorio, R. S. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179936 · Cited by 216 · see citing works
Lutsey, P. L., Misialek, J. R., Mosley, T. H., Gottesman, R. F., Punjabi, N. M., Shahar, E., MacLehose, R., Ogilvie, R. P., Knopman, D., & Alonso, A. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.06.2269 · Cited by 198 · see citing works
The links between the gut microbiome, aging, modern lifestyle and Alzheimer's disease
Askarova, S., Umbayev, B., Masoud, A.-R., Kaiyrlykyzy, A., Safarova, Y., Tsoy, A., Olzhayev, F., & Kushugulova, A. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00104 · Cited by 208 · see citing works
Di Meco, A., Joshi, Y. B., & Praticò, D. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.02.011 · Cited by 205 · see citing works
Varga, A. W., Wohlleber, M. E., Giménez, S., Romero, S., Alonso, J. F., Ducca, E. L., Kam, K., Lewis, C., Tanzi, E. B., Tweardy, S., et al. (2016) · SLEEP · doi:10.5665/sleep.6240 · Cited by 203 · see citing works
Branger, P., Arenaza-Urquijo, E. M., Tomadesso, C., Mézenge, F., André, C., de Flores, R., Mutlu, J., de La Sayette, V., Eustache, F., Chételat, G., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.02.009 · Cited by 186 · see citing works
Sleep-Wake Disturbances After Traumatic Brain Injury: Synthesis of Human and Animal Studies
Sandsmark, D. K., Elliott, J. E., & Lim, M. M. (2017) · Sleep · doi:10.1093/sleep/zsx044 · Cited by 183 · see citing works
Self-citationRothman, S. M., Herdener, N., Frankola, K. A., Mughal, M. R., & Mattson, M. P. (2013) · Brain Research · doi:10.1016/j.brainres.2013.07.010 · Cited by 172 · see citing works
The sleep–wake Cycle and Alzheimer’s Disease: What do We know?
Lim, M. M., Gerstner, J. R., & Holtzman, D. M. (2014) · Neurodegenerative Disease Management · doi:10.2217/nmt.14.33 · Cited by 168 · see citing works
Self-citationSleep Interacts with Aβ to Modulate Intrinsic Neuronal Excitability
Tabuchi, M., Lone, S. R., Liu, S., Liu, Q., Zhang, J., Spira, A. P., & Wu, M. N. (2015) · Current Biology · doi:10.1016/j.cub.2015.01.016 · Cited by 165 · see citing works
Circadian disruption and human health: A bidirectional relationship
Abbott, S. M., Malkani, R. G., & Zee, P. C. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14298 · Cited by 161 · see citing works
Ishiki, A., Kamada, M., Kawamura, Y., Terao, C., Shimoda, F., Tomita, N., Arai, H., & Furukawa, K. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13399 · Cited by 156 · see citing works
Boutoleau-Bretonnière, C., Pouclet-Courtemanche, H., Gillet, A., Bernard, A., Deruet, A. L., Gouraud, I., Mazoue, A., Lamy, E., Rocher, L., Kapogiannis, D., et al. (2020) · Journal of Alzheimer's Disease · doi:10.3233/jad-200604 · Cited by 151 · see citing works
Sleep disturbances and dementia risk: a multicenter study
Sindi, S., Kåreholt, I., Johansson, L., Skoog, J., Sjöberg, L., Wang, H., Johansson, B., Fratiglioni, L., Soininen, H., Solomon, A., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.05.012 · Cited by 144 · see citing works
Rainey-Smith, S. R., Mazzucchelli, G. N., Villemagne, V. L., Brown, B. M., Porter, T., Weinborn, M., Bucks, R. S., Milicic, L., Sohrabi, H. R., Taddei, K., et al. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0094-x · Cited by 144 · see citing works
Evidence for Neuroinflammatory and Microglial Changes in the Cerebral Response to Sleep Loss
Wisor, J. P., Schmidt, M. A., & Clegern, W. C. (2011) · Sleep · doi:10.1093/sleep/34.3.261 · Cited by 141 · see citing works
Blackman, J., Swirski, M., Clynes, J., Harding, S., Leng, Y., & Coulthard, E. (2021) · Journal of Sleep Research · doi:10.1111/jsr.13229 · Cited by 141 · see citing works
Cleaning the sleeping brain – the potential restorative function of the glymphatic system
Hauglund, N. L., Pavan, C., & Nedergaard, M. (2020) · Current Opinion in Physiology · doi:10.1016/j.cophys.2019.10.020 · Cited by 129 · see citing works
The discovery of suvorexant, the first orexin receptor drug for insomnia
Coleman, P. J., Gotter, A. L., Herring, W. J., Winrow, C. J., & Renger, J. J. (2017) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104837 · Cited by 128 · see citing works
Emerging links between type 2 diabetes and Alzheimer's disease
Sridhar, G. R. (2015) · World Journal of Diabetes · doi:10.4239/wjd.v6.i5.744 · Cited by 123 · see citing works
Liang, Y., Qu, L.-B., & Liu, H. (2019) · Aging Clinical and Experimental Research · doi:10.1007/s40520-018-1005-y · Cited by 116 · see citing works
Kincheski, G. C., Valentim, I. S., Clarke, J. R., Cozachenco, D., Castelo-Branco, M. T. L., Ramos-Lobo, A. M., Rumjanek, V. M. B. D., Donato, J., De Felice, F. G., & Ferreira, S. T. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2017.04.007 · Cited by 117 · see citing works
Hong, S., Quintero-Monzon, O., Ostaszewski, B. L., Podlisny, D. R., Cavanaugh, W. T., Yang, T., Holtzman, D. M., Cirrito, J. R., & Selkoe, D. J. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3272-11.2011 · Cited by 111 · see citing works
Self-citationDevore, E. E., Grodstein, F., & Schernhammer, E. S. (2016) · Neuroepidemiology · doi:10.1159/000442418 · Cited by 107 · see citing works
Fan, L., Xu, W., Cai, Y., Hu, Y., & Wu, C. (2019) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2019.06.009 · Cited by 96 · see citing works
Zhao, N., Chen, Q.-G., Chen, X., Liu, X.-T., Geng, F., Zhu, M.-M., Yan, F.-L., Zhang, Z.-J., & Ren, Q.-G. (2023) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2022.11.013 · Cited by 105 · see citing works
The association between insomnia and cardiovascular diseases
Spiegelhalder, K. (2010) · Nature and Science of Sleep · doi:10.2147/nss.s7471 · Cited by 107 · see citing works
Cao, J., Herman, A. B., West, G. B., Poe, G., & Savage, V. M. (2020) · Science Advances · doi:10.1126/sciadv.aba0398 · Cited by 105 · see citing works
Altered CSF Orexin and α-Synuclein Levels in Dementia Patients
Wennström, M., Londos, E., Minthon, L., & Nielsen, H. M. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-111655 · Cited by 104 · see citing works
Sleep Disturbances in Alzheimer’s and Parkinson’s Diseases
Rothman, S. M., & Mattson, M. P. (2012) · NeuroMolecular Medicine · doi:10.1007/s12017-012-8181-2 · Cited by 102 · see citing works
Association of Sleep and β-Amyloid Pathology Among Older Cognitively Unimpaired Adults
Insel, P. S., Mohlenhoff, B. S., Neylan, T. C., Krystal, A. D., & Mackin, R. S. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.17573 · Cited by 97 · see citing works
Bokenberger, K., Ström, P., Dahl Aslan, A. K., Johansson, A. L. V., Gatz, M., Pedersen, N. L., & Åkerstedt, T. (2017) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glw127 · Cited by 96 · see citing works
Wu, L., Sun, D., & Tan, Y. (2018) · Sleep and Breathing · doi:10.1007/s11325-017-1527-0 · Cited by 90 · see citing works
Defining circadian disruption in neurodegenerative disorders
Colwell, C. S. (2021) · Journal of Clinical Investigation · doi:10.1172/jci148288 · Cited by 90 · see citing works
Benedict, C., Cedernaes, J., Giedraitis, V., Nilsson, E. K., Hogenkamp, P. S., Vågesjö, E., Massena, S., Pettersson, U., Christoffersson, G., Phillipson, M., et al. (2014) · Sleep · doi:10.5665/sleep.3336 · Cited by 86 · see citing works
Lutsey, P. L., Bengtson, L. G. S., Punjabi, N. M., Shahar, E., Mosley, T. H., Gottesman, R. F., Wruck, L. M., MacLehose, R. F., & Alonso, A. (2016) · Sleep · doi:10.5665/sleep.5434 · Cited by 86 · see citing works
Justice, N. J., Huang, L., Tian, J.-B., Cole, A., Pruski, M., Hunt, A. J., Flores, R., Zhu, M. X., Arenkiel, B. R., & Zheng, H. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.3333-14.2015 · Cited by 81 · see citing works
Neuropeptidergic control of sleep and wakefulness
Richter, C., Woods, I. G., & Schier, A. F. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-062111-150447 · Cited by 75 · see citing works
The why and how of sleep-dependent synaptic down-selection
Cirelli, C., & Tononi, G. (2022) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2021.02.007 · Cited by 74 · see citing works
Lloret, M.-A., Cervera-Ferri, A., Nepomuceno, M., Monllor, P., Esteve, D., & Lloret, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031168 · Cited by 68 · see citing works
Central and peripheral circadian clocks and their role in Alzheimer's disease
Chauhan, R., Chen, K.-F., Kent, B. A., & Crowther, D. C. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.030627 · Cited by 58 · see citing works
“For example, Aβ in the ISF is higher during wakefulness in mice, representing periods of peak neuronal activity (Bero et al., 2011), and lowest during sleep (Huang et al., 2012; Kang et al., 2009) or under anaesthesia (Brody et al., 2008).”
BackgroundInfluentialPrevalence of obstructive sleep apnea in Alzheimer’s disease patients
Gaeta, A. M., Benítez, I. D., Jorge, C., Torres, G., Dakterzada, F., Minguez, O., Huerto, R., Pujol, M., Carnes, A., Dalmases, M., et al. (2020) · Journal of Neurology · doi:10.1007/s00415-019-09668-4 · Cited by 55 · see citing works
Ridnour, L. A., Dhanapal, S., Hoos, M., Wilson, J., Lee, J., Cheng, R. Y. S., Brueggemann, E. E., Hines, H. B., Wilcock, D. M., Vitek, M. P., et al. (2012) · Journal of Neurochemistry · doi:10.1111/jnc.12028 · Cited by 54 · see citing works
Self-citationHerring, W. J., Roth, T., Krystal, A. D., & Michelson, D. (2019) · Journal of Sleep Research · doi:10.1111/jsr.12782 · Cited by 53 · see citing works
Aquaporin-4 and Cognitive Disorders
Wang, Y., Huang, C., Guo, Q., & Chu, H. (2022) · Aging and disease · doi:10.14336/ad.2021.0731 · Cited by 55 · see citing works
Kim, E., Nohara, K., Wirianto, M., Escobedo, G., Lim, J. Y., Morales, R., Yoo, S.-H., & Chen, Z. (2021) · Biomolecules · doi:10.3390/biom11071004 · Cited by 51 · see citing works
Is sleep disruption a risk factor for Alzheimer's disease?
Macedo, A. C., Balouch, S., & Tabet, N. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-161287 · Cited by 49 · see citing works
Herukka, S.-K., Rummukainen, J., Ihalainen, J., von und zu Fraunberg, M., Koivisto, A. M., Nerg, O., Puli, L. K., Seppälä, T. T., Zetterberg, H., Pyykkö, O. T., et al. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-142862 · Cited by 43 · see citing works
- Authors
- Kang, J.-E., Lim, M. M., Bateman, R. J., Lee, J. J., Smyth, L. P., Cirrito, J. R., Fujiki, N., Nishino, S., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Stanford Medicine (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Science
- Published
- 2009-11-13
- Volume
- 326
- Issue
- 5955
- Pages
- 1005-1007
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2789838
- OpenAlex
- W2013333500
- Cited by
- 1,565
- References
- 14
- Citations by year
- 2026: 108 · 2025: 120 · 2024: 124 · 2023: 112 · 2022: 111 · 2021: 136 · 2020: 131 · 2019: 111 · 2018: 98 · 2017: 97 · 2016: 87 · 2015: 79 · 2014: 70 · 2013: 55 · 2012: 45
- FWCI
- 28.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG 025824, AG030946, R01AG025824, K01AG029524, P50AG005681, K23AG030946, AG029524)
- National Institute of Mental Health (MH072525, R01MH072525)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056341)
- National Institute of Neurological Disorders and Stroke (NS065667, P30NS057105, R01NS065667)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, orexin, sleep-wake cycle, Alzheimer's disease, sleep deprivation, orexin receptor antagonists, brain interstitial fluid, amyloid plaques, amyloid precursor protein transgenic mice, amyloid-beta aggregation
- MeSH terms
- Orexins, Acetamides, Alzheimer Disease, Animals, Antigens, Surface, Circadian Rhythm, Disease Models, Animal, Female, Hippocampus, Humans, Isoquinolines, Light, Male, Mice, Inbred C57BL, Mice, Transgenic, Neuropeptides, Receptors, Cell Surface, Sleep, Sleep Deprivation, Wakefulness, Signal Transduction, Amyloid beta-Peptides, Receptors, Neuropeptide, Receptors, G-Protein-Coupled, Extracellular Fluid, Intracellular Signaling Peptides and Proteins, Mice, Orexin Receptors
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
