Skip to main content

Advertisement

SpringerLink
Log in

Circadian Rhythms in AD Pathogenesis: a Critical Appraisal

  • Circadian Rhythm Disorders (F Turek, Section Editor)
  • Published:
Current Sleep Medicine Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

A wide array of sleep and circadian deficits has been observed in patients with Alzheimer’s disease (AD). However, the vast majority of these studies have focused on later-stage AD and do not shed light on the possibility that circadian dysfunction contributes to AD pathogenesis. The goal of this review is to examine the evidence supporting or refuting the hypothesis that circadian dysfunction plays an important role in early AD pathogenesis or AD risk in humans.

Recent Findings

Few studies have addressed the role of the circadian system in very early AD or prior to AD diagnosis. AD appears to have a long presymptomatic phase during which pathology is present, but cognition remains normal. Studies evaluating circadian function in cognitively normal elderly or early-stage AD have thus far not incorporated AD biomarkers. Thus, the cause-and-effect relationship between circadian dysfunction and early-stage AD remains unclear.

Summary

Circadian dysfunction becomes apparent in AD as dementia progresses, but it is unknown at which point in the pathogenic process rhythms begin to deteriorate. Further, it is unknown if exposure to circadian disruption in middle age increases AD risk later in life. This review addresses gaps in current knowledge on this topic and proposes several critical directions for future research which might help to clarify the potential pathogenic role of circadian clock dysfunction in AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Alzheimer’s Association. Alzhiemer’s disease facts and figures. Alzheimers Dement. 2015;11:332–84.

    Article  Google Scholar 

  2. Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A. Sundowning and circadian rhythms in Alzheimer’s disease. Am J Psychiatry. 2001;158:704–11. doi:10.1176/appi.ajp.158.5.704.

    Article  CAS  PubMed  Google Scholar 

  3. Holth JK, Patel TK, Holtzman DM. Sleep in Alzheimer’s disease-beyond amyloid. Neurobiol Sleep Circad Rhythym. 2016; doi:10.1016/j.nbscr.2016.08.002.

    Google Scholar 

  4. Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology—a bidirectional relationship. Nat Rev Neurol. 2014;10:115–9. doi:10.1038/nrneurol.2013.269.

    Article  CAS  PubMed  Google Scholar 

  5. Musiek ES, Xiong DD, Holtzman DM. Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med. 2015;47:e148. doi:10.1038/emm.2014.121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Peter-Derex L, Yammine P, Bastuji H, Croisile B. Sleep and Alzheimer’s disease. Sleep Med Rev. 2014;19:29–38.

    Article  PubMed  Google Scholar 

  7. McClung CR. Plant circadian rhythms. Plant Cell. 2006;18:792–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Edgar RS, Green EW, Zhao Y, van Ooijen G, Olmedo M, Qin X, et al. Peroxiredoxins are conserved markers of circadian rhythms. Nature. 2012;485:459–64. doi:10.1038/nature11088.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012;35:445–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Herzog ED, Hermanstyne T, Smyllie NJ, Hastings MH. Regulating the suprachiasmatic nucleus (SCN) circadian clockwork: interplay between cell-autonomous and circuit-level mechanisms. Cold Spring Harb Perspect Biol. 2017;9:a027706. doi:10.1101/cshperspect.a027706.

    Article  PubMed  Google Scholar 

  11. Colwell CS. Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci. 2011;12:553–69. doi:10.1038/nrn3086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kalsbeek A, Fliers E, Hofman MA, Swaab DF, Buijs RM. Vasopressin and the output of the hypothalamic biological clock. J Neuroendocrinol. 2010;22:362–72. doi:10.1111/j.1365-2826.2010.01956.x.

    Article  CAS  PubMed  Google Scholar 

  13. Yamaguchi Y, Suzuki T, Mizoro Y, Kori H, Okada K, Chen Y, et al. Mice genetically deficient in vasopressin V1a and V1b receptors are resistant to jet lag. Science. 2013;342:85–90. doi:10.1126/science.1238599.

    Article  CAS  PubMed  Google Scholar 

  14. Aton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci. 2005;8:476–83. doi:10.1038/nn1419.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. An S, Harang R, Meeker K, Granados-Fuentes D, Tsai CA, Mazuski C, et al. A neuropeptide speeds circadian entrainment by reducing intercellular synchrony. Proc Natl Acad Sci U S A. 2013;110:E4355–61. doi:10.1073/pnas.1307088110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kudo T, Tahara Y, Gamble KL, McMahon DG, Block GD, Colwell CS. Vasoactive intestinal peptide produces long-lasting changes in neural activity in the suprachiasmatic nucleus. J Neurophysiol. 2013;110:1097–106. doi:10.1152/jn.00114.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Prolo LM, Takahashi JS, Herzog ED. Circadian rhythm generation and entrainment in astrocytes. J Neurosci. 2005;25:404–8.

    Article  CAS  PubMed  Google Scholar 

  18. Webb AB, Angelo N, Huettner JE, Herzog ED. Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons. Proc Natl Acad Sci U S A. 2009;106:16493–8. doi:10.1073/pnas.0902768106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Snider KH, Dziema H, Aten S, Loeser J, Norona FE, Hoyt K, et al. Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits. Behav Brain Res. 2016;308:222–35. doi:10.1016/j.bbr.2016.04.027.

    Article  CAS  PubMed  Google Scholar 

  20. Barca-Mayo O, Pons-Espinal M, Follert P, Armirotti A, Berdondini L, De Pietri TD. Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling. Nat Commun. 2017;8:14336. doi:10.1038/ncomms14336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nakazato R, Hotta S, Yamada D, Kou M, Nakamura S, Takahata Y, et al. The intrinsic microglial clock system regulates interleukin-6 expression. Glia. 2017;65:198–208. doi:10.1002/glia.23087.

    Article  PubMed  Google Scholar 

  22. Fonken LK, Frank MG, Kitt MM, Barrientos RM, Watkins LR, Maier SF. Microglia inflammatory responses are controlled by an intrinsic circadian clock. Brain Behav Immun. 2015;45:171–9. doi:10.1016/j.bbi.2014.11.009.

    Article  CAS  PubMed  Google Scholar 

  23. Forman BM, Chen J, Blumberg B, Kliewer SA, Henshaw R, Ong ES, et al. Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors. Mol Endocrinol. 1994;8:1253–61. doi:10.1210/mend.8.9.7838158.

    CAS  PubMed  Google Scholar 

  24. Ptitsyn AA, Zvonic S, Conrad SA, Scott LK, Mynatt RL, Gimble JM. Circadian clocks are resounding in peripheral tissues. PLoS Comput Biol. 2006;2:e16. doi:10.1371/journal.pcbi.0020016.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci U S A. 2014;111:16219–24. doi:10.1073/pnas.1408886111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dallmann R, Viola AU, Tarokh L, Cajochen C, Brown SA. The human circadian metabolome. Proc Natl Acad Sci U S A. 2012;109:2625–9. doi:10.1073/pnas.1114410109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466:627–31. doi:10.1038/nature09253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Anea CB, Zhang M, Stepp DW, Simkins GB, Reed G, Fulton DJ, et al. Vascular disease in mice with a dysfunctional circadian clock. Circulation. 2009;119:1510–7. doi:10.1161/CIRCULATIONAHA.108.827477.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Huo M, Huang Y, Qu D, Zhang H, Wong WT, Chawla A, et al. Myeloid Bmal1 deletion increases monocyte recruitment and worsens atherosclerosis. FASEB J. 2016; doi:10.1096/fj.201601030R.

    PubMed  Google Scholar 

  30. Nguyen KD, Fentress SJ, Qiu Y, Yun K, Cox JS, Chawla A. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science. 2013;341:1483–8. doi:10.1126/science.1240636.

    Article  CAS  PubMed  Google Scholar 

  31. Curtis AM, Fagundes CT, Yang G, Palsson-McDermott EM, Wochal P, McGettrick AF, et al. Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1. Proc Natl Acad Sci U S A. 2015;112:7231–6. doi:10.1073/pnas.1501327112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J Clin Invest. 2013;123:5389–400. doi:10.1172/JCI70317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Knutsson A, Kempe A. Shift work and diabetes—a systematic review. Chronobiol Int. 2014;31:1146–51. doi:10.3109/07420528.2014.957308.

    Article  PubMed  Google Scholar 

  34. Davis S, Mirick DK, Stevens RG. Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst. 2001;93:1557–62.

    Article  CAS  PubMed  Google Scholar 

  35. Vetter C, Devore EE, Wegrzyn LR, Massa J, Speizer FE, Kawachi I, et al. Association between rotating night shift work and risk of coronary heart disease among women. JAMA. 2016;315:1726–34. doi:10.1001/jama.2016.4454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kecklund G, Axelsson J. Health consequences of shift work and insufficient sleep. BMJ. 2016;355:i5210.

    Article  PubMed  Google Scholar 

  37. Loewenstein RJ, Weingartner H, Gillin JC, Kaye W, Ebert M, Mendelson WB. Disturbances of sleep and cognitive functioning in patients with dementia. Neurobiol Aging. 1982;3:371–7.

    Article  CAS  PubMed  Google Scholar 

  38. Vitiello MV, Prinz PN. Alzheimer’s disease. Sleep and sleep/wake patterns. Clin Geriatr Med. 1989;5:289–99.

    CAS  PubMed  Google Scholar 

  39. Witting W, Kwa IH, Eikelenboom P, Mirmiran M, Swaab DF. Alterations in the circadian rest-activity rhythm in aging and Alzheimer’s disease. Biol Psychiatry. 1990;27:563–72.

    Article  CAS  PubMed  Google Scholar 

  40. Okawa M, Mishima K, Hishikawa Y, Hozumi S, Hori H, Takahashi K. Circadian rhythm disorders in sleep-waking and body temperature in elderly patients with dementia and their treatment. Sleep. 1991;14:478–85.

    Article  CAS  PubMed  Google Scholar 

  41. Ancoli-Israel S, Cole R, Alessi C, Chambers M, Moorcroft W, Pollak CP. The role of actigraphy in the study of sleep and circadian rhythms. Sleep. 2003;26:342–92.

    Article  PubMed  Google Scholar 

  42. Satlin A, Volicer L, Stopa EG, Harper D. Circadian locomotor activity and core-body temperature rhythms in Alzheimer’s disease. Neurobiol Aging. 1995;16:765–71.

    Article  CAS  PubMed  Google Scholar 

  43. Ancoli-Israel S, Klauber MR, Jones DW, Kripke DF, Martin J, Mason W, et al. Variations in circadian rhythms of activity, sleep, and light exposure related to dementia in nursing-home patients. Sleep. 1997;20:18–23.

    Article  CAS  PubMed  Google Scholar 

  44. Harper DG, Volicer L, Stopa EG, McKee AC, Nitta M, Satlin A. Disturbance of endogenous circadian rhythm in aging and Alzheimer disease. Am J Geriatr Psychiatry. 2005;13:359–68. doi:10.1176/appi.ajgp.13.5.359.

    Article  PubMed  Google Scholar 

  45. Uchida K, Okamoto N, Ohara K, Morita Y. Daily rhythm of serum melatonin in patients with dementia of the degenerate type. Brain Res. 1996;717:154–9.

    Article  CAS  PubMed  Google Scholar 

  46. Prinz PN, Christie C, Smallwood R, Vitaliano P, Bokan J, Vitiello MV, et al. Circadian temperature variation in healthy aged and in Alzheimer’s disease. J Gerontol. 1984;39:30–5.

    Article  CAS  PubMed  Google Scholar 

  47. Weissova K, Bartos A, Sladek M, Novakova M, Sumova A. Moderate changes in the circadian system of Alzheimer’s disease patients detected in their home environment. PLoS One. 2016;11:e0146200. doi:10.1371/journal.pone.0146200.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hatfield CF, Herbert J, van Someren EJ, Hodges JR, Hastings MH. Disrupted daily activity/rest cycles in relation to daily cortisol rhythms of home-dwelling patients with early Alzheimer’s dementia. Brain. 2004;127:1061–74. doi:10.1093/brain/awh129.

    Article  CAS  PubMed  Google Scholar 

  49. Gehrman P, Marler M, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. The relationship between dementia severity and rest/activity circadian rhythms. Neuropsychiatr Dis Treat. 2005;1:155–63.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Mieda M, Okamoto H, Sakurai T. Manipulating the cellular circadian period of arginine vasopressin neurons alters the behavioral circadian period. Curr Biol. 2016;26:2535–42. doi:10.1016/j.cub.2016.07.022.

    Article  CAS  PubMed  Google Scholar 

  51. • Wang JL, Lim AS, Chiang WY, Hsieh WH, Lo MT, Schneider JA, et al. Suprachiasmatic neuron numbers and rest-activity circadian rhythms in older humans. Ann Neurol. 2015;78:317–22. doi:10.1002/ana.24432. Provides correlation between circadian rhythms and SCN VIP neuron count.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Swaab DF, Fliers E, Partiman TS. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res. 1985;342:37–44.

    Article  CAS  PubMed  Google Scholar 

  53. Zhou JN, Hofman MA, Swaab DF. VIP neurons in the human SCN in relation to sex, age, and Alzheimer’s disease. Neurobiol Aging. 1995;16:571–6.

    Article  CAS  PubMed  Google Scholar 

  54. Wu YH, Zhou JN, Van Heerikhuize J, Jockers R, Swaab DF. Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer’s disease. Neurobiol Aging. 2007;28:1239–47. doi:10.1016/j.neurobiolaging.2006.06.002.

    Article  CAS  PubMed  Google Scholar 

  55. Harper DG, Stopa EG, Kuo-Leblanc V, McKee AC, Asayama K, Volicer L, et al. Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia. Brain. 2008;131:1609–17. doi:10.1093/brain/awn049.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wu YH, Fischer DF, Kalsbeek A, Garidou-Boof ML, van der Vliet J, van Heijningen C, et al. Pineal clock gene oscillation is disturbed in Alzheimer’s disease, due to functional disconnection from the “master clock”. FASEB J. 2006;20:1874–6. doi:10.1096/fj.05-4446fje.

    Article  CAS  PubMed  Google Scholar 

  57. Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, Okawa M. Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep-waking. Biol Psychiatry. 1999;45:417–21.

    Article  CAS  PubMed  Google Scholar 

  58. Skene DJ, Vivien-Roels B, Sparks DL, Hunsaker JC, Pevet P, Ravid D, et al. Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer’s disease. Brain Res. 1990;528:170–4.

    Article  CAS  PubMed  Google Scholar 

  59. Skene DJ, Swaab DF. Melatonin rhythmicity: effect of age and Alzheimer’s disease. Exp Gerontol. 2003;38:199–206.

    Article  CAS  PubMed  Google Scholar 

  60. Lim AS, Myers AJ, Yu L, Buchman AS, Duffy JF, De Jager PL, et al. Sex difference in daily rhythms of clock gene expression in the aged human cerebral cortex. J Biol Rhythm. 2013;28:117–29. doi:10.1177/0748730413478552.

    Article  CAS  Google Scholar 

  61. Chen CY, Logan RW, Ma T, Lewis DA, Tseng GC, Sibille E, et al. Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proc Natl Acad Sci U S A. 2016;113:206–11. doi:10.1073/pnas.1508249112.

    Article  CAS  PubMed  Google Scholar 

  62. Cermakian N, Lamont EW, Boudreau P, Boivin DB. Circadian clock gene expression in brain regions of Alzheimer’s disease patients and control subjects. J Biol Rhythm. 2011;26:160–70. doi:10.1177/0748730410395732.

    Article  Google Scholar 

  63. Azzi A, Dallmann R, Casserly A, Rehrauer H, Patrignani A, Maier B, et al. Circadian behavior is light-reprogrammed by plastic DNA methylation. Nat Neurosci. 2014;17:377–82. doi:10.1038/nn.3651.

    Article  CAS  PubMed  Google Scholar 

  64. Lim AS, Srivastava GP, Yu L, Chibnik LB, Xu J, Buchman AS, et al. 24-hour rhythms of DNA methylation and their relation with rhythms of RNA expression in the human dorsolateral prefrontal cortex. PLoS Genet. 2014;10:e1004792. doi:10.1371/journal.pgen.1004792.

    Article  PubMed  PubMed Central  Google Scholar 

  65. • Cronin P, McCarthy MJ, Lim AS, Salmon DP, Galasko D, Masliah E, et al. Circadian alterations during early stages of Alzheimer’s disease are associated with aberrant cycles of DNA methylation in BMAL1. Alzheimers Dement. 2016; doi:10.1016/j.jalz.2016.10.003. First demonstration of altered Bmal1 promoter methylation in AD.

    PubMed  Google Scholar 

  66. Kawas CH, Kim RC, Sonnen JA, Bullain SS, Trieu T, Corrada MM. Multiple pathologies are common and related to dementia in the oldest-old: The 90+ Study. Neurology. 2015;85:535–42. doi:10.1212/wnl.0000000000001831.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Toledo JB, Cairns NJ, Da X, Chen K, Carter D, Fleisher A, et al. Clinical and multimodal biomarker correlates of ADNI neuropathological findings. Acta Neuropathol Commun. 2013;1:65. doi:10.1186/2051-5960-1-65.

    Article  PubMed  PubMed Central  Google Scholar 

  68. McAleese KE, Walker L, Erskine D, Thomas AJ, McKeith IG, Attems J. TDP-43 pathology in Alzheimer’s disease, dementia with Lewy bodies and ageing. Brain Pathol. 2016; doi:10.1111/bpa.12424.

    PubMed  Google Scholar 

  69. Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med. 2011;3:77sr1. doi:10.1126/scitranslmed.3002369.

    PubMed  PubMed Central  Google Scholar 

  70. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–19. doi:10.1002/ana.20009.

    Article  CAS  PubMed  Google Scholar 

  71. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280–92. doi:10.1016/j.jalz.2011.03.003.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Jack Jr CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9:119–28. doi:10.1016/s1474-4422(09)70299-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, et al. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2013;12:957–65. doi:10.1016/s1474-4422(13)70194-7.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Roe CM, Fagan AM, Grant EA, Hassenstab J, Moulder KL, Maue Dreyfus D, et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology. 2013;80:1784–91. doi:10.1212/WNL.0b013e3182918ca6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12:357–67. doi:10.1016/s1474-4422(13)70044-9.

    Article  CAS  PubMed  Google Scholar 

  76. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature. 2009;461:916–22. doi:10.1038/nature08538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367:795–804. doi:10.1056/NEJMoa1202753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–9. doi:10.1016/j.jalz.2011.03.008.

    Article  PubMed  PubMed Central  Google Scholar 

  79. • Naismith SL, Hickie IB, Terpening Z, Rajaratnam SM, Hodges JR, Bolitho S, et al. Circadian misalignment and sleep disruption in mild cognitive impairment. J Alzheimers Dis. 2014;38:857–66. doi:10.3233/jad-131217. This is one of the only papers examining sleep changes in mild cognitive impairment.

    CAS  PubMed  Google Scholar 

  80. •• Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013;70:587–93. doi:10.1001/jamaneurol.2013.2334. This is the only paper to date examining the relationship between CSF Aβ biomarker status and sleep parameters in cognitively normal people.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Tranah GJ, Blackwell T, Stone KL, Ancoli-Israel S, Paudel ML, Ensrud KE, et al. Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women. Ann Neurol. 2011;70:722–32.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313:1924–38. doi:10.1001/jama.2015.4668.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA. Sleep fragmentation and the risk of incident Alzheimer’s disease and cognitive decline in older persons. Sleep. 2013;36:1027–32. doi:10.5665/sleep.2802.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Hahn EA, Wang HX, Andel R, Fratiglioni L. A change in sleep pattern may predict Alzheimer disease. Am J Geriatr Psychiatry. 2014;22:1262–71.

    Article  PubMed  Google Scholar 

  85. Spira AP, Gamaldo AA, An Y, Wu MN, Simonsick EM, Bilgel M, et al. Self-reported sleep and beta-amyloid deposition in community-dwelling older adults. JAMA Neurol. 2013;70:1537–43. doi:10.1001/jamaneurol.2013.4258.

    PubMed  PubMed Central  Google Scholar 

  86. Sterniczuk R, Theou O, Rusak B, Rockwood K. Sleep disturbance is associated with incident dementia and mortality. Curr Alzheimer Res. 2013;10:767–75.

    Article  CAS  PubMed  Google Scholar 

  87. • Mander BA, Marks SM, Vogel JW, Rao V, Lu B, Saletin JM, et al. Beta-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci. 2015;18:1051–7. doi:10.1038/nn.4035. Explores a unique potential mechanism linking Aβ pathology to SWS disruption.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Potvin O, Lorrain D, Forget H, Dube M, Grenier S, Preville M, et al. Sleep quality and 1-year incident cognitive impairment in community-dwelling older adults. Sleep. 2012;35:491–9. doi:10.5665/sleep.1732.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Cho K. Chronic ‘jet lag’ produces temporal lobe atrophy and spatial cognitive deficits. Nat Neurosci. 2001;4:567–8. doi:10.1038/88384.

    Article  CAS  PubMed  Google Scholar 

  90. Cho K, Ennaceur A, Cole JC, Suh CK. Chronic jet lag produces cognitive deficits. J Neurosci. 2000;20:RC66.

    CAS  PubMed  Google Scholar 

  91. Ma D, Panda S, Lin JD. Temporal orchestration of circadian autophagy rhythm by C/EBPbeta. EMBO J. 2011;30:4642–51. doi:10.1038/emboj.2011.322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4:147ra111. doi:10.1126/scitranslmed.3003748.

    Article  PubMed  PubMed Central  Google Scholar 

  93. • Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342:373–7. doi:10.1126/science.1241224. First description of a role for sleep in the regulation of the glymphatic clearance system.

    Article  CAS  PubMed  Google Scholar 

  94. Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123:1299–309. doi:10.1172/JCI67677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Erik S. Musiek is funded by NINDS K08 award K08NS079405 and an award from the Coins for Alzheimer’s Trust (CART).

Author information

Authors and Affiliations

  1. Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, 425 South Euclid Ave, Box 8111, Saint Louis, MO, 63110, USA

    Erik S. Musiek

Authors
  1. Erik S. Musiek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erik S. Musiek.

Ethics declarations

Conflict of Interest

Erik S. Musiek reports grants from NIH, Alzheimer’s Association, Coins for Alzheimer’s Trust, during the conduct of the study; personal fees from Eisai Pharmaceuticals.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Circadian Rhythm Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Musiek, E.S. Circadian Rhythms in AD Pathogenesis: a Critical Appraisal. Curr Sleep Medicine Rep 3, 85–92 (2017). https://doi.org/10.1007/s40675-017-0072-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40675-017-0072-5

Keywords

Search

Navigation