Mechanisms linking circadian clocks, sleep, and neurodegeneration
Open accessAbstract
Disruptions of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly affect health. Accumulating evidence indicates that circadian and sleep disturbances, which have long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this Review, we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer’s disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging.
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?
Circadian rhythm disruption, often from irregular sleep-wake cycles, impairs glymphatic clearance of neurotoxic metabolites like amyloid-beta, exacerbating cognitive decline.
“Circadian rhythm disruption, often resulting from irregular sleep-wake cycles, impairs glymphatic clearance of neurotoxic metabolites like amyloid-β, exacerbating cognitive decline [5].”
From What Are the Key Biological Pathways Through Which Lifestyle Factors Influence Neurodegeneration? (2025) · cites this paper as [5]
In “Sleep and Neurodegeneration” (page not specified), the review reports that slow-wave sleep increases glymphatic clearance of Aβ in mice and that sleep disturbances can affect cognition. But it explicitly says the effect of chronic sleep disturbances on glymphatic function remains uncertain; it does not establish that circadian disruption impairs that clearance and thereby exacerbates cognitive decline. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe survey finding that diet type and sleep duration were associated with belief in preventability aligns with biological evidence on diet and circadian regulation in modulating neuroinflammation and glymphatic clearance.
“This aligns with biological evidence highlighting the roles of diet and circadian regulation in modulating neuroinflammation and glymphatic clearance [4,5].”
From What Are the Key Biological Pathways Through Which Lifestyle Factors Influence Neurodegeneration? (2025) · cites this paper as [5]
The Inflammation section links circadian clocks to inflammatory responses, and Sleep and Neurodegeneration reports that slow-wave sleep increased glymphatic flow and amyloid-beta clearance in mice. The paper does not establish that diet type modulates neuroinflammation or glymphatic clearance; its discussion of feeding rhythms does not support that part of the claim. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDiffusion MRI indicates age-related changes in white matter connectivity between prefrontal and posterior cortical regions and within posterior sensory cortices.
“Diffusion MRI methods have shown age-related changes in white matter connectivity between prefrontal and posterior cortical regions, and within posterior sensory cortices.25–27”
From Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing (2018) · cites this paper as [25]
The Sleep and Neurodegeneration section discusses sleep, synaptic function, and medial prefrontal amyloid pathology, while the Circadian function and neurodegeneration section discusses age-related circadian changes. Neither addresses diffusion MRI or the specified age-related white matter connectivity changes. Searches for diffusion MRI and for connectivity in posterior sensory cortices found no supporting passage in our copy; page numbers were unavailable. (LLM, conf=0.76)
Experimental — accuracy not yet measuredAcute administration of ibuprofen led to a delay of SWS in addition to its sleep-disrupting effect.
“Acute administration of ibuprofen, in addition to its sleep disrupting effect, also led to a delay of SWS (398).”
From The Sleep-Immune Crosstalk in Health and Disease (2019) · cites this paper as [398]
Acute administration of aspirin at the recommended daily dose range in healthy participants disrupted sleep (decreased sleep efficiency, increased number of awakenings) and decreased SWS.
“acute administration of aspirin at the recommended daily dose range in healthy participants disrupted sleep (i.e., decreased sleep efficiency, increased number of awakenings) (398) and decreased SWS (241).”
From The Sleep-Immune Crosstalk in Health and Disease (2019) · cites this paper as [398]
There is accumulating evidence linking disrupted sleep and circadian rhythms to neurodegenerative disorders in humans and animal models.
“There is also accumulating evidence linking disrupted sleep and circadian rhythms to neurodegenerative disorders in humans and animal models235,236.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [236]
Older people (ages ~65 years and older) generally sleep less and have poorer sleep efficiency, increased night-time awakening, increased sleep latency and greater levels of daytime sleepiness.
“Older people (ages ~65 years and older) generally sleep less and have poorer sleep efficiency, increased night-time awakening, increased sleep latency and greater levels of daytime sleepiness234–236.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [236]
The build-up and expulsion of reactive oxygen species follow a circadian pattern.
“The build-up and expulsion of reactive oxygen species (ROS) also follow a circadian pattern.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [236]
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
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 · see citing works
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
Tononi, G., & Cirelli, C. (2014) · Neuron · doi:10.1016/j.neuron.2013.12.025 · Cited by 2,356 · see citing works
A circadian gene expression atlas in mammals: Implications for biology and medicine
Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E., & Hogenesch, J. B. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408886111 · Cited by 2,304 · see citing works
Central and Peripheral Circadian Clocks in Mammals
Mohawk, J. A., Green, C. B., & Takahashi, J. S. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-060909-153128 · Cited by 2,265 · see citing works
Circadian integration of metabolism and energetics
Bass, J., & Takahashi, J. S. (2010) · Science · doi:10.1126/science.1195027 · Cited by 1,910 · see citing works
Mop3 is an essential component of the master circadian pacemaker in mammals.
Bunger, M. K., Wilsbacher, L. D., Moran, S. M., Clendenin, C., Radcliffe, L. A., Hogenesch, J. B., Simon, M. C., Takahashi, J. S., & Bradfield, C. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00205-1 · Cited by 1,621 · see citing works
Amyloid-β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle
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. (2009) · Science · doi:10.1126/science.1180962 · Cited by 1,565 · see citing works
Self-citationAn h <i>Per2</i> Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome
Toh, K. L., Jones, C. R., He, Y., Eide, E. J., Hinz, W. A., Virshup, D. M., Ptáček, L. J., & Fu, Y.-H. (2001) · Science · doi:10.1126/science.1057499 · Cited by 1,460 · see citing works
Circadian Control of the NAD <sup>+</sup> Salvage Pathway by CLOCK-SIRT1
Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M., & Sassone-Corsi, P. (2009) · Science · doi:10.1126/science.1170803 · Cited by 1,198 · see citing works
Kondratov, R. V., Kondratova, A. A., Gorbacheva, V. Y., Vykhovanets, O. V., & Antoch, M. P. (2006) · Genes & Development · doi:10.1101/gad.1432206 · Cited by 1,188 · see citing works
Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD <sup>+</sup> Biosynthesis
Ramsey, K. M., Yoshino, J., Brace, C. S., Abrassart, D., Kobayashi, Y., Marcheva, B., Hong, H.-K., Chong, J. L., Buhr, E. D., Lee, C., et al. (2009) · Science · doi:10.1126/science.1171641 · Cited by 1,126 · see citing works
Peroxiredoxins are conserved markers of circadian rhythms
Edgar, R. S., Green, E. W., Zhao, Y., Gerben Van Ooijen, A., Olmedo, M., Qin, X., Xu, Y. Q., Pan, M., Valekunja, U. K., Feeney, K. A., et al. (2012) · Nature · doi:10.1038/nature11088 · Cited by 915 · see citing works
The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia
Swaab, D. F., Fliers, E., & Partiman, T. S. (1985) · Brain Research · doi:10.1016/0006-8993(85)91350-2 · Cited by 847 · see citing works
A circadian clock in macrophages controls inflammatory immune responses
Keller, M., Mazuch, J., Abraham, U., Eom, G. D., Herzog, E. D., Volk, H.-D., Kramer, A., & Maier, B. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906361106 · Cited by 843 · see citing works
Schenck, C. H., Boeve, B. F., & Mahowald, M. W. (2013) · Sleep Medicine · doi:10.1016/j.sleep.2012.10.009 · Cited by 814 · see citing works
Riemersma-van der Lek, R. F. (2008) · JAMA · doi:10.1001/jama.299.22.2642 · Cited by 803 · see citing works
Lim, 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
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-citationThree dimensions of the amyloid hypothesis: time, space and 'wingmen'
Musiek, E. S., & Holtzman, D. M. (2015) · Nature Neuroscience · doi:10.1038/nn.4018 · Cited by 697 · see citing works
Self-citationGibbs, J. E., Blaikley, J., Beesley, S., Matthews, L. C., Simpson, K. D., Boyce, S., Farrow, S. N., Else, K. J., Singh, D., Ray, D. W., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106750109 · Cited by 671 · see citing works
Circadian Gene Bmal1 Regulates Diurnal Oscillations of Ly6C hi Inflammatory Monocytes
Nguyen, K. D., Fentress, S. J., Qiu, Y., Yun, K., Cox, J. S., & Chawla, A. (2013) · Science · doi:10.1126/science.1240636 · Cited by 647 · see citing works
SIRT1 Mediates Central Circadian Control in the SCN by a Mechanism that Decays with Aging
Chang, H.-C., & Guarente, L. (2013) · Cell · doi:10.1016/j.cell.2013.05.027 · Cited by 615 · see citing works
Roh, 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-citationMukherji, A., Kobiita, A., Ye, T., & Chambon, P. (2013) · Cell · doi:10.1016/j.cell.2013.04.020 · Cited by 560 · see citing works
Disruption of circadian clocks has ramifications for metabolism, brain, and behavior
Karatsoreos, I. N., Bhagat, S., Bloss, E. B., Morrison, J. H., & McEwen, B. S. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1018375108 · Cited by 547 · see citing works
β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation
Mander, B. A., Marks, S. M., Vogel, J. W., Rao, V. R., Lu, B. S., Saletin, J., Ancoli‐Israel, S., Jagust, W. J., & Walker, M. P. (2015) · Nature Neuroscience · doi:10.1038/nn.4035 · Cited by 546 · see citing works
Dysregulation of inflammatory responses by chronic circadian disruption
Castanon-Cervantes, O., Wu, M., Ehlen, J. C., Paul, K., Gamble, K. L., Johnson, R. L., Besing, R. C., Menaker, M., Gewirtz, A. T., & Davidson, A. J. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001026 · Cited by 542 · see citing works
Tranah, 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 clock proteins regulate neuronal redox homeostasis and neurodegeneration
Musiek, E. S., Lim, M. M., Yang, G., Bauer, A. Q., Qi, L., Lee, Y., Roh, J. H., Ortiz-Gonzalez, X., Dearborn, J. T., Culver, J. P., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci70317 · Cited by 524 · see citing works
Self-citationSleep and Circadian Rhythm Regulation in Early Parkinson Disease
Breen, D. P., Vuono, R., Nawarathna, U., Fisher, K., Shneerson, J. M., Reddy, A. B., & Barker, R. A. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.65 · Cited by 440 · see citing works
Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease
Morton, A. J., Wood, N. I., Hastings, M. H., Hurelbrink, C., Barker, R. A., & Maywood, E. S. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3842-04.2005 · Cited by 403 · see citing works
Circadian Melatonin Rhythm and Excessive Daytime Sleepiness in Parkinson Disease
Videnovic, A., Noble, C., Reid, K. J., Peng, J., Turek, F. W., Marconi, A., Rademaker, A. W., Simuni, T., Zadikoff, C., & Zee, P. C. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.6239 · Cited by 390 · see citing works
Age-Related Decline in Circadian Output
Nakamura, T. J., Nakamura, W., Yamazaki, S., Kudo, T., Cutler, T., Colwell, C. S., & Block, G. D. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0451-11.2011 · Cited by 386 · see citing works
'The clocks that time us'—circadian rhythms in neurodegenerative disorders
Videnović, A., Lázár, A. S., Barker, R. A., & Overeem, S. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.206 · Cited by 373 · see citing works
A Drosophila model for age-associated changes in sleep:wake cycles
Koh, K., Evans, J. M., Hendricks, J. C., & Sehgal, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605903103 · Cited by 341 · see citing works
Chronic 'jet lag' produces temporal lobe atrophy and spatial cognitive deficits
Cho, K. (2001) · Nature Neuroscience · doi:10.1038/88384 · Cited by 332 · see citing works
The effects of 40 hours of total sleep deprivation on inflammatory markers in healthy young adults
Frey, D. J., Fleshner, M., & Wright, K. P. (2007) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2007.04.003 · Cited by 330 · see citing works
Hatfield, C. F. (2004) · Brain · doi:10.1093/brain/awh129 · Cited by 323 · see citing works
Timing of expression of the core clock gene Bmal1 influences its effects on aging and survival
Yang, G., Chen, L., Grant, G. R., Paschos, G. K., Song, W., Musiek, E. S., Lee, V., McLoughlin, S. C., Großer, T., Cotsarelis, G., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad3305 · Cited by 317 · see citing works
Self-citationCircadian control of innate immunity in macrophages by miR-155 targeting <i>Bmal1</i>
Curtis, A. M., Fagundes, C. T., Yang, G., Palsson-McDermott, E. M., Wochal, P., McGettrick, A. F., Foley, N. H., Early, J. O., Chen, L., Zhang, H., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1501327112 · Cited by 311 · see citing works
Laposky, A. D., Easton, A. E., Dugovic, C., Walisser, J. A., Bradfield, C. A., & Turek, F. W. (2005) · SLEEP · doi:10.1093/sleep/28.4.395 · Cited by 297 · see citing works
Circadian Rhythm Generation and Entrainment in Astrocytes
Prolo, L. M., Takahashi, J. S., & Herzog, E. D. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4133-04.2005 · Cited by 294 · see citing works
Aging Impairs the Unfolded Protein Response to Sleep Deprivation and Leads to Proapoptotic Signaling
Naidoo, N. N., Ferber, M., Master, M., Zhu, Y., & Pack, A. I. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5685-07.2008 · Cited by 282 · see citing works
Effects of Age and Amyloid Deposition on Aβ Dynamics in the Human Central Nervous System
Huang, Y. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.235 · Cited by 281 · see citing works
Microglia inflammatory responses are controlled by an intrinsic circadian clock
Fonken, L. K., Frank, M. G., Kitt, M. M., Barrientos, R. M., Watkins, L. R., & Maier, S. F. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.11.009 · Cited by 280 · see citing works
Loss of circadian rhythm in sleep-wakefulness cycle in the rat by suprachiasmatic nucleus lesions
Ibuka, N., & Kawamura, H. (1975) · Brain Research · doi:10.1016/0006-8993(75)90574-0 · Cited by 271 · see citing works
Temporal orchestration of circadian autophagy rhythm by C/EBPβ
Ma, D., Panda, S., & Lin, J. D. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.322 · Cited by 234 · see citing works
Circadian regulation of hippocampal long-term potentiation
Chaudhury, D., Wang, L. M., & Colwell, C. S. (2005) · Journal of Biological Rhythms · doi:10.1177/0748730405276352 · Cited by 231 · see citing works
Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease
Roh, J. H., Jiang, H., Finn, M. B., Stewart, F. R., Mahan, T. E., Cirrito, J. R., Heda, A., Snider, B. J., Li, M., Yanagisawa, M., et al. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20141788 · Cited by 230 · see citing works
Self-citationReinke, H., Saini, C., Fleury-Olela, F., Dibner, C., Benjamin, I. J., & Schibler, U. (2008) · Genes & Development · doi:10.1101/gad.453808 · Cited by 228 · see citing works
Circadian Rhythm of Redox State Regulates Excitability in Suprachiasmatic Nucleus Neurons
Wang, T. A., Yu, Y. V., Govindaiah, G., Ye, X., Artinian, L. R., Coleman, T. P., Sweedler, J. V., Cox, C. L., & Gillette, M. U. (2012) · Science · doi:10.1126/science.1222826 · Cited by 221 · see citing works
Suprachiasmatic neuron numbers and rest–activity circadian rhythms in older humans
Wang, J. L., Lim, A. S., Chiang, W., Hsieh, W., Lo, M., Schneider, J. A., Buchman, A. S., Bennett, D. A., Hu, K., & Saper, C. B. (2015) · Annals of Neurology · doi:10.1002/ana.24432 · Cited by 217 · 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
Characterization of the 3xTg-AD mouse model of Alzheimer's disease: Part 1. Circadian changes
Sterniczuk, R., Dyck, R. H., LaFerla, F. M., & Antle, M. C. (2010) · Brain Research · doi:10.1016/j.brainres.2010.05.013 · Cited by 198 · see citing works
Gibson, E. M., Wang, C., Tjho, S., Khattar, N., & Kriegsfeld, L. J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015267 · Cited by 196 · see citing works
Forbes, D., Blake, C. M., Thiessen, E. J., Peacock, S., & Hawranik, P. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003946.pub4 · Cited by 194 · see citing works
Pallier, P. N., Maywood, E. S., Zheng, Z., Chesham, J. E., Inyushkin, A. N., Dyball, R. E. J., Hastings, M. H., & Morton, A. J. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0649-07.2007 · Cited by 193 · see citing works
Hayashi, Y., Koyanagi, S., Kusunose, N., Okada, R., Wu, Z., Tozaki‐Saitoh, H., Ukai, K., Kohsaka, S., Inoue, K., Ohdo, S., et al. (2013) · Scientific Reports · doi:10.1038/srep02744 · Cited by 192 · see citing works
Cedernaes, J., Osler, M. E., Voisin, S., Broman, J.-E., Vogel, H., Dickson, S. L., Zierath, J. R., Schiöth, H. B., & Benedict, C. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2284 · Cited by 188 · see citing works
Circadian dysfunction in a mouse model of Parkinson's disease
Kudo, T., Loh, D. H., Truong, D., Wu, Y., & Colwell, C. S. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.08.003 · Cited by 188 · see citing works
Sleep Disturbance is Associated with Incident Dementia and Mortality
Sterniczuk, R., Theou, O., Rusak, B., & Rockwood, K. J. (2013) · Current Alzheimer Research · doi:10.2174/15672050113109990134 · Cited by 185 · see citing works
Cai, Y., Liu, S., Sothern, R. B., Xu, S., & Chan, P. (2010) · European Journal of Neurology · doi:10.1111/j.1468-1331.2009.02848.x · Cited by 184 · see citing works
Cermakian, N., Waddington Lamont, E., Boudreau, P., & Boivin, D. B. (2011) · Journal of Biological Rhythms · doi:10.1177/0748730410395732 · Cited by 175 · see citing works
Rothman, 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
Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons
Zhang, J., Zhu, Y., Zhan, G., Fenik, P., Panossian, L., Wang, M. M., Reid, S., Lai, D., Davis, J. G., Baur, J. A., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.5025-12.2014 · Cited by 171 · see citing works
Impact of aging on diurnal expression patterns of CLOCK and BMAL1 in the mouse brain
Wyse, C. A., & Coogan, A. N. (2010) · Brain Research · doi:10.1016/j.brainres.2010.03.113 · Cited by 167 · see citing works
A time to remember: The role of circadian clocks in learning and memory.
Smarr, B. L., Jennings, K. J., Driscoll, J. R., & Kriegsfeld, L. J. (2014) · Behavioral Neuroscience · doi:10.1037/a0035963 · Cited by 166 · see citing works
Sleep in Alzheimer's Disease–Beyond Amyloid
Holth, J. K., Patel, T. K., & Holtzman, D. M. (2016) · Neurobiology of Sleep and Circadian Rhythms · doi:10.1016/j.nbscr.2016.08.002 · Cited by 165 · see citing works
Self-citationDysfunctions in circadian behavior and physiology in mouse models of Huntington's disease
Kudo, T., Schroeder, A., Loh, D. H., Kuljis, D. A., Jordan, M. C., Roos, K. P., & Colwell, C. S. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.12.011 · Cited by 163 · see citing works
Self‐reported sleep disturbance is associated with Alzheimer's disease risk in men
Benedict, C., Byberg, L., Cedernaes, J., Hogenkamp, P. S., Giedratis, V., Kilander, L., Lind, L., Lannfelt, L., & Schiöth, H. B. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.08.104 · Cited by 160 · see citing works
Aβ-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer’s disease
Song, H., Moon, M., Choe, H. K., Han, D.-H., Jang, C., Kim, A., Cho, S., Kim, K., & Mook‐Jung, I. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0007-x · Cited by 154 · see citing works
Bouchard-Cannon, P., Mendoza-Viveros, L., Yuen, A., Kærn, M., & Cheng, H. M. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.10.037 · Cited by 154 · see citing works
Circadian clock protein BMAL1 regulates cellular senescence in vivo
Khapre, R. V., Kondratova, A. A., Susova, O. Y., & Kondratov, R. V. (2011) · Cell Cycle · doi:10.4161/cc.10.23.18381 · Cited by 138 · see citing works
Daily rhythm of serum melatonin in patients with dementia of the degenerate type
Uchida, K., Okamoto, N., Ohara, K., & Morita, Y. (1996) · Brain Research · doi:10.1016/0006-8993(96)00086-8 · Cited by 138 · see citing works
Maywood, E. S., Fraenkel, E., McAllister, C., Wood, N. I., Reddy, A. B., Hastings, M. H., & Morton, A. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1694-10.2010 · Cited by 135 · see citing works
Mongrain, V., La Spada, F., Curie, T., & Franken, P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026622 · Cited by 118 · see citing works
Sleep deficits but no metabolic deficits in premanifest H untington's disease
Lázár, A. S., Panin, F., Goodman, A. O. G., Lazic, S. E., Lázár, Z. I., Mason, S., Rogers, L., Murgatroyd, P. R., Watson, L. P. E., Singh, P., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24495 · Cited by 116 · see citing works
Stratmann, M., Suter, D. M., Molina, N., Naef, F., & Schibler, U. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.08.012 · Cited by 115 · see citing works
Genetic disruption of the core circadian clock impairs hippocampus-dependent memoryPreprint
Wardlaw, S. M., Phan, T., Saraf, A., Chen, X., & Storm, D. R. (2014) · Learning & Memory · doi:10.1101/lm.035451.114 · Cited by 113 · 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
Association of ARNTL and PER1 genes with Parkinson's disease: a case-control study of Han Chinese
Gu, Z., Wang, B., Zhang, Y., Ding, H., Zhang, Y., Yu, J. M., Gu, M., Chan, P., & Cai, Y. (2015) · Scientific Reports · doi:10.1038/srep15891 · Cited by 104 · see citing works
Huang, G., Zhang, F.-M., Ye, Q., & Wang, H. (2016) · Autophagy · doi:10.1080/15548627.2016.1183843 · Cited by 104 · see citing works
Sleep in Neurodegenerative Diseases
Iranzo, Á. (2016) · Sleep Medicine Clinics · doi:10.1016/j.jsmc.2015.10.011 · Cited by 95 · see citing works
Earnest, D. J., & Turek, F. W. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.12.4277 · Cited by 94 · see citing works
BMAL1 controls the diurnal rhythm and set point for electrical seizure threshold in mice
Gerstner, J. R., Smith, G. G., Lenz, O., et al. (2014) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2014.00121 · Cited by 92 · see citing works
Circadian Regulation of Glutathione Levels and Biosynthesis in Drosophila melanogaster
Beaver, L. M., Klichko, V. I., Chow, E. S., Kotwica‐Rolinska, J., Williamson, M., Orr, W. C., Radyuk, S. N., & Giebultowicz, J. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050454 · Cited by 87 · 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
Curie, T., Maret, S., Emmenegger, Y., & Franken, P. (2015) · SLEEP · doi:10.5665/sleep.4974 · Cited by 67 · see citing works
Osorio, R. S., Ducca, E. L., Wohlleber, M. E., Tanzi, E. B., Gumb, T., Twumasi, A., Tweardy, S., Lewis, C., Fischer, E., Koushyk, V., et al. (2016) · SLEEP · doi:10.5665/sleep.5846 · Cited by 64 · see citing works
Premature aging of the hippocampal neurogenic niche in adult Bmal1‐ deficient mice
Ali, A. A. H., Schwarz‐Herzke, B., Stahr, A., Prozorovski, T., Aktaş, O., & von Gall, C. (2015) · Aging · doi:10.18632/aging.100764 · Cited by 59 · see citing works
Misaligned feeding impairs memories
Loh, D. H., Jami, S. A., Flores, R. E., Truong, D. A., Ghiani, C. A., O’Dell, T. J., & Colwell, C. S. (2015) · eLife · doi:10.7554/elife.09460 · Cited by 52 · see citing works
Chen, H.-F., Huang, C.-Q., You, C., Wang, Z.-R., & Si-qing, H. (2013) · Archives of Medical Research · doi:10.1016/j.arcmed.2013.01.002 · Cited by 48 · see citing works
Circadian Oscillations of Molecular Clock Components in the Cerebellar Cortex of the Rat
Rath, M. F., Rohde, K., & Møller, M. (2012) · Chronobiology International · doi:10.3109/07420528.2012.728660 · Cited by 42 · see citing works
Chen, Q., Peng, X. D., Huang, C. Q., Hu, X. Y., & Zhang, X. M. (2015) · Genetics and Molecular Research · doi:10.4238/2015.december.23.39 · Cited by 37 · see citing works
Survival of Adult Generated Hippocampal Neurons Is Altered in Circadian Arrhythmic Mice
Rakai, B. D., Chrusch, M. J., Spanswick, S. C., Dyck, R. H., & Antle, M. C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099527 · Cited by 34 · see citing works
Circadian modulation of proteasome activities and removal of carbonylated proteins
Desvergne, A., Ugarte, N., Petropoulos, I., & Friguet, B. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.10.631 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing
Cabeza, R., Albert, M., Belleville, S., Craik, F. I. M., Duarte, A., Grady, C. L., Lindenberger, U., Nyberg, L., Park, D. C., Reuter-Lorenz, P. A., et al. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0068-2 · Cited by 1,289 · see citing works
A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain
Wang, J., Gu, B. J., Masters, C. L., & Wang, Y.-J. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.111 · Cited by 808 · see citing works
Rhythms 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
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-citationCircadian disruption and human health
Fishbein, A. B., Knutson, K. L., & Zee, P. C. (2021) · Journal of Clinical Investigation · doi:10.1172/jci148286 · Cited by 468 · see citing works
Butterfield, D. A., & Boyd-Kimball, D. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170543 · Cited by 403 · see citing works
Stowell, R. D., Sipe, G. O., Dawes, R. P., Batchelor, H. N., Lordy, K. A., Whitelaw, B. S., Stoessel, M. B., Bidlack, J. M., Brown, E., Sur, M., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0514-0 · Cited by 321 · see citing works
Wang, Z., Chen, W.-H., Li, S.-X., He, Z.-M., Zhu, W.-L., Ji, Y.-B., Wang, Z., Zhu, X.-M., Yuan, K., Bao, Y.-P., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01113-1 · Cited by 307 · see citing works
Emerging roles of innate and adaptive immunity in Alzheimer’s disease
Chen, X., & Holtzman, D. M. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.016 · Cited by 297 · see citing works
Self-citationMerikangas, K. R., Swendsen, J., Hickie, I. B., Cui, L., Shou, H., Merikangas, A. K., Zhang, J., Lamers, F., Crainiceanu, C., Volkow, N. D., et al. (2019) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2018.3546 · Cited by 231 · see citing works
Therapeutic Approach to Alzheimer’s Disease: Current Treatments and New Perspectives
Pardo-Moreno, T., González-Acedo, A., Rivas-Domínguez, A., García-Morales, V., García-Cozar, F. J., Ramos-Rodríguez, J. J., & Melguizo-Rodríguez, L. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14061117 · Cited by 239 · 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
Lananna, B. V., McKee, C. A., King, M. W., Del-Aguila, J. L., Dimitry, J. M., Farias, F. H. G., Nadarajah, C. J., Xiong, D. D., Guo, C., Cammack, A. J., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aax3519 · Cited by 201 · see citing works
Self-citationAxonal Degeneration during Aging and Its Functional Role in Neurodegenerative Disorders
Salvadores, N., Sanhueza, M., Manque, P., & Court, F. A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00451 · Cited by 182 · see citing works
Vercruysse, P., Vieau, D., Blum, D., Petersén, Å., & Dupuis, L. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00002 · Cited by 172 · see citing works
Circadian disruption and sleep disorders in neurodegeneration
Shen, Y., Lv, Q.-K., Xie, W.-Y., Gong, S.-Y., Zhuang, S., Liu, J.-Y., Mao, C.-J., & Liu, C.-F. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00340-6 · Cited by 171 · see citing works
Sundaram, S., Hughes, R. L., Peterson, E., Müller-Oehring, E. M., Brontë-Stewart, H. M., Poston, K. L., Faerman, A., Bhowmick, C., & Schulte, T. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.05.016 · Cited by 152 · see citing works
Ma, W., Song, J., Wang, H., Shi, F., Zhou, N., Jiang, J., Xu, Y., Zhang, L., Yang, L., & Zhou, M. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.04.006 · Cited by 134 · 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
Origins of human disease: the chrono-epigenetic perspective
Oh, E. S., & Petronis, A. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00348-6 · Cited by 108 · 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
Defining circadian disruption in neurodegenerative disorders
Colwell, C. S. (2021) · Journal of Clinical Investigation · doi:10.1172/jci148288 · Cited by 90 · see citing works
Hoyt, K. R., & Obrietan, K. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00537-9 · Cited by 77 · 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
“Sleep disruption and risk of amyloid pathology As recounted above and elsewhere (Holth et al., 2017; Ju et al., 2014; Musiek and Holtzman, 2016; Musiek et al., 2015), neurodegenerative disease results in the loss of restorative sleep, which might in turn accentuate the pathological processes that contribute to AD.”
BackgroundShou, H., Cui, L., Hickie, I., Lameira, D., Lamers, F., Zhang, J., Crainiceanu, C., Zipunnikov, V, & Merikangas, K. R. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.136 · Cited by 53 · 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
The Molecular Clock and Neurodegenerative Disease: A Stressful Time
Carter, B., Justin, H. S., Gulick, D., & Gamsby, J. J. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.644747 · Cited by 42 · see citing works
Huang, Z., Liu, Q., Peng, Y., Dai, J., Xie, Y., Chen, W., Long, S., Pei, Z., Su, H., & Yao, X. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00218 · Cited by 38 · see citing works
Pinto, A. P., Muñoz, V. R., da Rocha, A. L., Rovina, R. L., Ferrari, G. D., Alberici, L. C., Simabuco, F. M., Teixeira, G. R., Pauli, J. R., de Moura, L. P., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.953272 · Cited by 14 · see citing works
Making Memories: Why Time Matters
Kelley, P., Evans, M. D. R., & Kelley, J. (2018) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2018.00400 · Cited by 10 · see citing works
Familiarity of Brazilian psychologists with basic concepts in sleep science and chronobiology
Marilac Soalheiro, L., de Jesus Brandão, B., Paiva, R. V. N., Dias Carvalho, L., Menezes Paranhos, R. D., Ribeiro Barbosa, P. C., Guerrero-Vargas, N. N., & Tamura, E. K. (2023) · Chronobiology International · doi:10.1080/07420528.2023.2250870 · Cited by 5 · see citing works
Deep Trans-Omic Network Fusion for Molecular Mechanism of Alzheimer’s Disease
Xie, L., Raj, Y., Varathan, P., He, B., Yu, M., Nho, K., Salama, P., Saykin, A. J., & Yan, J. (2024) · Journal of Alzheimer's Disease · doi:10.3233/jad-240098 · Cited by 2 · see citing works
What Are the Key Biological Pathways Through Which Lifestyle Factors Influence Neurodegeneration?
Su, Z. (2025) · Theoretical and Natural Science · doi:10.54254/2753-8818/2025.au25765
- Authors
- Musiek, E. S., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Musiek, Erik S.
- Venue
- Science
- Published
- 2016-11-25
- Volume
- 354
- Issue
- 6315
- Pages
- 1004-1008
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5219881
- OpenAlex
- W2553026365
- Cited by
- 878
- References
- 97
- Citations by year
- 2026: 121 · 2025: 135 · 2024: 106 · 2023: 93 · 2022: 87 · 2021: 87 · 2020: 79 · 2019: 63 · 2018: 65 · 2017: 42
- FWCI
- 6.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (K08NS079405, P01NS074969)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Keywords
- circadian rhythm, sleep, neurodegeneration, Alzheimer's disease, clock genes, sleep deprivation, brain homeostasis, aging, circadian rhythm disruption, therapeutic target
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain, Circadian Rhythm, Humans, Sleep, Suprachiasmatic Nucleus, Dyssomnias, Mice, Circadian Clocks
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
