Orexin and Alzheimer’s Disease

  • Claudio LiguoriEmail author
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)


Alzheimer’s disease (AD) is the most frequent age-related dementia. It prevalently causes cognitive decline, although it is frequently associated with secondary behavioral disturbances. AD neurodegeneration characteristically produces a remarkable destruction of the sleep–wake cycle, with diurnal napping, nighttime arousals, sleep fragmentation, and REM sleep impairment. It was recently hypothesized that the orexinergic system was involved in AD pathology. Accordingly, recent papers showed the association between orexinergic neurotransmission dysfunction, sleep impairment, and cognitive decline in AD. Orexin is a hypothalamic neurotransmitter which physiologically produces wakefulness and reduces REM sleep and may alter the sleep–wake cycle in AD patients. Furthermore, the orexinergic system seems to interact with CSF AD biomarkers, such as beta-amyloid and tau proteins. Beta-amyloid accumulation is the main hallmark of AD pathology, while tau proteins mark brain neuronal injury due to AD pathology. Investigations so far suggest that orexinergic signaling overexpression alters the sleep–wake cycle and secondarily induces beta-amyloid accumulation and tau-mediated neurodegeneration. Therefore, considering that orexinergic system dysregulation impairs sleep–wake rhythms and may influence AD pathology, it is hypothesized that orexin receptor antagonists are likely potential preventive/therapeutic options in AD patients.


Alzheimer’s disease Beta-amyloid Orexin Polysomnography REM Sleep disturbances Sleep–wake cycle Tau 


  1. 1.
    Alzheimer (1907) Über eine eigenartige Erkan kung der Hirnrinde. Psych Genchtl Med 64:146–148Google Scholar
  2. 2.
    Blessed G, Tomilson B-E, Roth M (1968) The association between quantitative measures of dementia, and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry 114:797–811CrossRefGoogle Scholar
  3. 3.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259CrossRefGoogle Scholar
  4. 4.
    Sperling RA, Jack CR Jr, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ (2011) Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement 7(4):367–385. doi: 10.1016/j.jalz.2011.05.2351 (Review)CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mander BA, Winer JR, Jagust WJ, Walker MP (2016) Sleep: a novel mechanistic pathway, biomarker, and treatment target in the pathology of Alzheimer's disease? Trends Neurosci 39(8):552–566CrossRefGoogle Scholar
  6. 6.
    Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A, Albanese M, Mercuri NB, Izzi F, Bernardini S, Nitti A, Sancesario GM, Sica F, Marciani MG, Placidi F (2014) Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol 71(12):1498–1505. doi: 10.1001/jamaneurol.2014.2510CrossRefPubMedGoogle Scholar
  7. 7.
    Liguori C, Placidi F, Albanese M, Nuccetelli M, Izzi F, Marciani MG, Mercuri NB, Bernardini S, Romigi A (2014) CSF beta-amyloid levels are altered in narcolepsy: a link with the inflammatory hypothesis? J Sleep Res 23(4):420–424CrossRefGoogle Scholar
  8. 8.
    Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M (2013) Sleep drives metabolite clearance from the adult brain. Science 342(6156):373–377. doi: 10.1126/science.1241224CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cricco M, Simonsick EM, Foley DJ (2001) The impact of insomnia on cognitive functioning in older adults. J Am Geriatr Soc 49(9):1185–1189CrossRefGoogle Scholar
  10. 10.
    Nebes RD, Buysse DJ, Halligan EM, Houck PR, Monk TH (2009) Self-reported sleep quality predicts poor cognitive performance in healthy older adults. J Gerontol B Psychol Sci Soc Sci 64(2):180–187. doi: 10.1093/geronb/gbn037 (Epub 9 Feb 2009)CrossRefPubMedGoogle Scholar
  11. 11.
    Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA (2014) Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol 71(8):971–977CrossRefGoogle Scholar
  12. 12.
    Peter-Derex L, Magnin M, Bastuji H (2015) Heterogeneity of arousals in human sleep: a stereo-electroencephalographic study. Neuroimage 123:229–244. doi: 10.1016/j.neuroimage.2015.07.057 (Epub 26 July 2015)CrossRefPubMedGoogle Scholar
  13. 13.
    Peng W, Achariyar TM, Li B, Liao Y, Mestre H, Hitomi E, Regan S, Kasper T, Peng S, Ding F, Benveniste H, Nedergaard M, Deane R (2016) Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol Dis 93:215–225CrossRefGoogle Scholar
  14. 14.
    McCurry SM, Logsdon RG, Vitiello MV, Teri L (2004) Treatment of sleep and nighttime disturbances in Alzheimer’s disease: a behavior management approach. Sleep Med 5(4):373–377CrossRefGoogle Scholar
  15. 15.
    Moran M, Lynch CA, Walsh C, Coen R, Coakley D, Lawlor BA (2005) Sleep disturbance in mild to moderate Alzheimer’s disease. Sleep Med 6(4):347–352 (Epub 31 Mar 2005)CrossRefGoogle Scholar
  16. 16.
    Vitiello MV, Prinz PN (1989) Alzheimer’s disease. Sleep and sleep/wake patterns. Clin Geriatr Med 5(2):289–299CrossRefGoogle Scholar
  17. 17.
    Osorio RS, Gumb T, Pirraglia E, Varga AW, Lu SE, Lim J, Wohlleber ME, Ducca EL, Koushyk V, Glodzik L, Mosconi L, Ayappa I, Rapoport DM, de Leon MJ (2015) Alzheimer’s disease neuroimaging initiative. Sleep-disordered breathing advances cognitive decline in the elderly. Neurology 84(19):1964–1971CrossRefGoogle Scholar
  18. 18.
    Troussière AC, Charley CM, Salleron J, Richard F, Delbeuck X, Derambure P, Pasquier F, Bombois S (2014) Treatment of sleep apnoea syndrome decreases cognitive decline in patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 85(12):1405–1408CrossRefGoogle Scholar
  19. 19.
    Kondratova AA, Kondratov RV (2012) The circadian clock and pathology of the ageing brain. Nat Rev Neurosci 13(5):325–335. doi: 10.1038/nrn3208 (Review)CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and circadian rhythms. Nature 437(7063):1257–1263CrossRefGoogle Scholar
  21. 21.
    Rosenzweig ES, Barnes CA (2003) Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Prog Neurobiol 69(3):143–179CrossRefGoogle Scholar
  22. 22.
    de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95(1):322–327CrossRefGoogle Scholar
  23. 23.
    Deadwyler SA, Porrino L, Siegel JM, Hampson RE (2007) Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 27(52):14239–14247CrossRefGoogle Scholar
  24. 24.
    Jaeger LB, Farr SA, Banks WA, Morley JE (2002) Effects of orexin-A on memory processing. Peptides 23(9):1683–1688CrossRefGoogle Scholar
  25. 25.
    Mavanji V, Perez-Leighton CE, Kotz CM, Billington CJ, Parthasarathy S, Sinton CM, Teske JA (2015) Promotion of wakefulness and energy expenditure by orexin-A in the ventrolateral preoptic area. Sleep 38(9):1361–1370CrossRefGoogle Scholar
  26. 26.
    Stanley EM, Fadel JR (2011) Aging-related alterations in orexin/hypocretin modulation of septo-hippocampal amino acid neurotransmission. Neuroscience 195:70–79CrossRefGoogle Scholar
  27. 27.
    Scheurink AJ, Boersma GJ, Nergårdh R, Södersten P (2010) Neurobiology of hyperactivity and reward: agreeable restlessness in anorexia nervosa. Physiol Behav 100(5):490–495CrossRefGoogle Scholar
  28. 28.
    Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L (2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci U S A 109(42):E2895–E2903CrossRefGoogle Scholar
  29. 29.
    Uslaner JM, Tye SJ, Eddins DM, et al. (2013) Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. Sci Transl Med 5(179):179ra44CrossRefGoogle Scholar
  30. 30.
    Dietrich H, Jenck F (2010) Intact learning and memory in rats following treatment with the dual orexin receptor antagonist almorexant. Psychopharmacology (Berl) 212(2):145–154CrossRefGoogle Scholar
  31. 31.
    Schmidt FM, Kratzsch J, Gertz HJ, Tittmann M, Jahn I, Pietsch UC, Kaisers UX, Thiery J, Hegerl U, Schönknecht P (2013) Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer’s disease. PLoS One 8(5):e63136. doi: 10.1371/journal.pone.0063136 (Print 2013)CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hirtz C, Vialaret J, Gabelle A, Nowak N, Dauvilliers Y, Lehmann S (2016) From radioimmunoassay to mass spectrometry: a new method to quantify orexin-A (hypocretin-1) in cerebrospinal fluid. Sci Rep 6:25162CrossRefGoogle Scholar
  33. 33.
    McGregor R, Wu MF, Barber G, Ramanathan L, Siegel JM (2011) Highly specific role of hypocretin (orexin) neurons: differential activation as a function of diurnal phase, operant reinforcement versus operant avoidance and light level. J Neurosci 31(43):15455–15467CrossRefGoogle Scholar
  34. 34.
    Boddum K, Hansen MH, Jennum PJ, Kornum BR (2016) Cerebrospinal fluid hypocretin-1 (orexin-A) level fluctuates with season and correlates with day length. PLoS One 11(3):e0151288CrossRefGoogle Scholar
  35. 35.
    Hunt NJ, Rodriguez ML, Waters KA, Machaalani R (2015) Changes in orexin (hypocretin) neuronal expression with normal aging in the human hypothalamus. Neurobiol Aging 36(1):292–300CrossRefGoogle Scholar
  36. 36.
    Ripley B, Overeem S, Fujiki N, Nevsimalova S, Uchino M, Yesavage J, Di Monte D, Dohi K, Melberg A, Lammers GJ, Nishida Y, Roelandse FW, Hungs M, Mignot E, Nishino S (2001) CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 57(12):2253–2258CrossRefGoogle Scholar
  37. 37.
    Baumann CR, Hersberger M, Bassetti CL (2006) Hypocretin-1 (orexin A) levels are normal in Huntington’s disease. J Neurol 253(9):1232–1233 (Epub 5 Apr 2006, No abstract available)CrossRefGoogle Scholar
  38. 38.
    Dauvilliers YA, Lehmann S, Jaussent I, Gabelle A (2014) Hypocretin and brain β-amyloid peptide interactions in cognitive disorders and narcolepsy. Front Aging Neurosci 6:119. doi: 10.3389/fnagi.2014.00119 (eCollection 2014)CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Deuschle M, Schilling C, Leweke FM, Enning F, Pollmächer T, Esselmann H, Wiltfang J, Frölich L, Heuser I (2014) Hypocretin in cerebrospinal fluid is positively correlated with Tau and pTau. Neurosci Lett 561:41–45. doi: 10.1016/j.neulet.2013.12.036 (Epub 25 Dec 2013)CrossRefPubMedGoogle Scholar
  40. 40.
    Liguori C, Nuccetelli M, Izzi F, Sancesario G, Romigi A, Martorana A, Amoros C, Bernardini S, Marciani MG, Mercuri NB, Placidi F (2016) Rapid eye movement sleep disruption and sleep fragmentation are associated with increased orexin-A cerebrospinal-fluid levels in mild cognitive impairment due to Alzheimer’s disease. Neurol Aging 40:120–126CrossRefGoogle Scholar
  41. 41.
    Fronczek R, van Geest S, Frölich M, Overeem S, Roelandse FW, Lammers GJ, Swaab DF (2012) Hypocretin (orexin) loss in Alzheimer’s disease. Neurobiol Aging 33(8):1642–1650. doi: 10.1016/j.neurobiolaging.2011.03.014 (Epub 5 May 2011)CrossRefPubMedGoogle Scholar
  42. 42.
    Gerashchenko D, Murillo-Rodriguez E, Lin L, Xu M, Hallett L, Nishino S, Mignot E, Shiromani PJ (2003) Relationship between CSF hypocretin levels and hypocretin neuronal loss. Exp Neurol 184(2):1010–1016CrossRefGoogle Scholar
  43. 43.
    Zhu Y, Fenik P, Zhan G, Somach R, Veasey RX (2016) Intermittent short sleep results in lasting sleep wake disturbances and degeneration of locus coeruleus and orexinergic neurons. Sleep 39(8):1601–1611. pii: sp-00094-16 (Epub ahead of print)CrossRefGoogle Scholar
  44. 44.
    Jones BE (2004) Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex. Prog Brain Res 145:157–169CrossRefGoogle Scholar
  45. 45.
    Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66(2):137–147CrossRefGoogle Scholar
  46. 46.
    Videnovic A, Zee PC (2015) Consequences of circadian disruption on neurologic health. Sleep Med Clin 10(4):469–480CrossRefGoogle Scholar
  47. 47.
    Stopa EG, Volicer L, Kuo-Leblanc V, Harper D, Lathi D, Tate B, Satlin A (1999) Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J Neuropathol Exp Neurol 58(1):29–39CrossRefGoogle Scholar
  48. 48.
    Wu YH, Feenstra MG, Zhou JN, Liu RY, Toranõ JS, Van Kan HJ, Fischer DF, Ravid R, Swaab DF (2003) Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab 88(12):5898–5906CrossRefGoogle Scholar
  49. 49.
    Wang JL, Lim AS, Chiang WY, et al. (2015) Suprachiasmatic neuron numbers and rest-activity circadian rhythms in older humans. Ann Neurol 78(2):317–322CrossRefGoogle Scholar
  50. 50.
    Friedman LF, Zeitzer JM, Lin L, Hoff D, Mignot E, Peskind ER, Yesavage JA (2007) Alzheimer disease, increased wake fragmentation found in those with lower hypocretin-1. Neurology 68(10):793–794 (No abstract available)CrossRefGoogle Scholar
  51. 51.
    Arrigoni E, Mochizuki T, Scammell TE (2010) Activation of the basal forebrain by the orexin/hypocretin neurones. Acta Physiol (Oxf) 198(3):223–235CrossRefGoogle Scholar
  52. 52.
    Lee MG, Hassani OK, Jones BE (2005) Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 25(28):6716–6720CrossRefGoogle Scholar
  53. 53.
    Beaulieu-Bonneau S, Hudon C (2009) Sleep disturbances in older adults with mild cognitive impairment. Int Psychogeriatr 21(4):654–666CrossRefGoogle Scholar
  54. 54.
    Bonanni E, Maestri M, Tognoni G et al (2005) Daytime sleepiness in mild and moderate Alzheimer’s disease and its relationship with cognitive impairment. J Sleep Res 14(3):311–317CrossRefGoogle Scholar
  55. 55.
    Montplaisir J, Petit D, Lorrain D et al (1995) Sleep in Alzheimer’s disease: further considerations on the role of brainstem and forebrain cholinergic populations in sleep-wake mechanisms. Sleep 18(3):145–148CrossRefGoogle Scholar
  56. 56.
    Maestri M, Carnicelli L, Tognoni G, Di Coscio E, Giorgi FS, Volpi L, Economou NT, Ktonas P, Ferri R, Bonuccelli U, Bonanni E (2015) Non-rapid eye movement sleep instability in mild cognitive impairment: a pilot study. Sleep Med 16(9):1139–1145CrossRefGoogle Scholar
  57. 57.
    Naismith SL, Hickie IB, Terpening Z, Rajaratnam SM, Hodges JR, Bolitho S, Rogers NL, Lewis SJ (2014) Circadian misalignment and sleep disruption in mild cognitive impairment. J Alzheimers Dis 38(4):857–866CrossRefGoogle Scholar
  58. 58.
    Ferrazzoli D, Sica F, Sancesario G (2013) Sundowning syndrome: a possible marker of frailty in Alzheimer's disease? CNS Neurol Disord Drug Targets 12(4):525–528CrossRefGoogle Scholar
  59. 59.
    Lin L, Huang QX, Yang SS, et al. (2013) Melatonin in Alzheimer’s disease. Int J Mol Sci 14(7):14575–14593CrossRefGoogle Scholar
  60. 60.
    Grothe M, Zaborszky L, Atienza M et al (2010) Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer’s disease. Cereb Cortex 20(7):1685–1695CrossRefGoogle Scholar
  61. 61.
    Kundermann B, Thum A, Rocamora R, Haag A, Krieg JC, Hemmeter U (2011) Comparison of polysomnographic variables and their relationship to cognitive impairment in patients with Alzheimer’s disease and frontotemporal dementia. J Psychiatr Res 45(12):1585–1592CrossRefGoogle Scholar
  62. 62.
    Mallick BN, Joseph MM (1997) Role of cholinergic inputs to the medial preoptic area in regulation of sleep-wakefulness and body temperature in freely moving rats. Brain Res 750:311–317CrossRefGoogle Scholar
  63. 63.
    Perry E, Walker M, Grace J, Perry R (1999) Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 22:273–280CrossRefGoogle Scholar
  64. 64.
    Power AE (2004) Slow-wave sleep, acetylcholine, and memory consolidation. Proc Natl Acad Sci U S A 101:1795–1796CrossRefGoogle Scholar
  65. 65.
    Eggermann E, Bayer L, Serafin M et al (2003) The wake-promoting hypocretin-orexin neurons are in an intrinsic state of membrane depolarization. J Neurosci 23(5):1557–1562CrossRefGoogle Scholar
  66. 66.
    Pedrazzoli M, D’Almeida V, Martins PJ et al (2004) Increased hypocretin-1 levels in cerebrospinal fluid after REM sleep deprivation. Brain Res 995(1):1–6CrossRefGoogle Scholar
  67. 67.
    Blennow K et al. (2016) Cerebrospinal fluid biomarkers in Alzheimer's and Parkinson's diseases-from pathophysiology to clinical practice. Mov Disord 31(6):836–847CrossRefGoogle Scholar
  68. 68.
    Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM (2009) Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326(5955):1005–1007. doi: 10.1126/science.1180962 (Epub 24 Sep 2009)CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Roh JH, Huang Y, Bero AW et al (2012) Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer’s disease pathology. Sci Transl Med 4(150):150ra122CrossRefGoogle Scholar
  70. 70.
    Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, Morris JC, Holtzman DM (2013) Sleep quality and preclinical Alzheimer disease. JAMA Neurol 70(5):587–593CrossRefGoogle Scholar
  71. 71.
    Roh JH, Jiang H, Finn MB, Stewart FR, Mahan TE, Cirrito JR, Heda A, Snider BJ, Li M, Yanagisawa M, de Lecea L, Holtzman DM (2014) Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease. J Exp Med 211(13):2487–2496. doi: 10.1084/jem.20141788CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Slats D, Claassen JA, Lammers GJ, Melis RJ, Verbeek MM, Overeem S (2012) Association between hypocretin-1 and amyloid-β42 cerebrospinal fluid levels in Alzheimer’s disease and healthy controls. Curr Alzheimer Res 9(10):1119–1125CrossRefGoogle Scholar
  73. 73.
    Wennström M, Londos E, Minthon L, Nielsen HM (2012) Altered CSF orexin and α-synuclein levels in dementia patients. J Alzheimers Dis 29(1):125–132. doi: 10.3233/JAD-2012-111655CrossRefPubMedGoogle Scholar
  74. 74.
    Osorio RS, Ducca EL, Wohlleber ME, Tanzi EB, Gumb T, Twumasi A, Tweardy S, Lewis C, Fischer E, Koushyk V, Cuartero-Toledo M, Sheikh MO, Pirraglia E, Zetterberg H, Blennow K, Lu SE, Mosconi L, Glodzik L, Schuetz S, Varga AW, Ayappa I, Rapoport DM, de Leon MJ (2016) Orexin-A is associated with increases in cerebrospinal fluid phosphorylated-tau in cognitively normal elderly subjects. Sleep 39(6):1253–1260CrossRefGoogle Scholar
  75. 75.
    Liguori C, Placidi F, Izzi F, et al. (2016) Beta-amyloid and phosphorylated tau metabolism changes in narcolepsy over time. Sleep Breath 20(1):277–283 discussion 283CrossRefGoogle Scholar
  76. 76.
    Hardy J (2009) The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J Neurochem 110:1129–1134CrossRefGoogle Scholar
  77. 77.
    Jack CR Jr, Knopman DS, Jagust WJ et al (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128CrossRefGoogle Scholar
  78. 78.
    Blennow K, Hampel H (2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2(10):605–613CrossRefGoogle Scholar
  79. 79.
    Kester MI, van der Vlies AE, Blankenstein MA et al (2009) CSF biomarkers predict rate of cognitive decline in Alzheimer disease. Neurology 73(17):1353–1358CrossRefGoogle Scholar
  80. 80.
    Yamada K, Holth JK, Liao F et al (2014) Neuronal activity regulates extracellular tau in vivo. J Exp Med 211(3):387–393. doi: 10.1084/jem.20131685 (Epub 17 Feb 2014)CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Di Meco et al (2014) NBAGoogle Scholar
  82. 82.
    Davies J, Chen J, Pink R, Carter D, Saunders N, Sotiriadis G, Bai B, Pan Y, Howlett D, Payne A, Randeva H, Karteris E (2015) Orexin receptors exert a neuroprotective effect in Alzheimer’s disease (AD) via heterodimerization with GPR103. Sci Rep 5:12584CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

Open Access This chapter is licensed under the terms of the Creative Commons Attribution-NonCommercial 2.5 International License (, which permits any noncommercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Authors and Affiliations

  1. 1.Sleep Medicine Centre, Neurophysiopathology Unit, Department of Systems MedicineUniversity of Rome “Tor Vergata”RomeItaly

Personalised recommendations