Advertisement

Revisiting the Cholinergic Hypothesis in Alzheimer’s Disease: Emerging Evidence from Translational and Clinical Research

  • Harald Hampel
  • M.-M. Mesulam
  • A. C. Cuello
  • A. S. Khachaturian
  • A. Vergallo
  • M. R. Farlow
  • P. J. Snyder
  • E. Giacobini
  • Z. S. Khachaturian
  • Cholinergic System Working Group, and for the Alzheimer Precision Medicine Initiative (APMI)
Review

Abstract

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer’s disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the “Cholinergic Hypothesis of AD” and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

Key words

Alzheimer’s disease cholinergic system cholinesterase inhibitors nucleus basalis of Meynert (NbM) degeneration nerve growth factor basal forebrain cholinergic system atrophy. 

Supplementary material

42414_2018_53_MOESM1_ESM.pdf (1.1 mb)
Memorandum of Understanding Among Harald Hampel, M-.Marsel Mesulam, A. Claudio Cuello, Ara S. Khachaturian, Martin R. Farlow, Peter J. Snyder, Ezio Giacobini, and Zaven S. Khachaturian

References

  1. 1.
    Khachaturian ZS, Khachaturian AS. Prevent Alzheimer’s disease by 2020: a national strategic goal. Alzheimers Dement. 2009;5:81–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Khachaturian ZS, Mesulam MM, Khachaturian AS, et al. The Special Topics Section of Alzheimer’s & Dementia. Alzheimers Dement. 2015;11:1261–4.PubMedCrossRefGoogle Scholar
  3. 3.
    OECD. OECD Analytical Report on Dementia: Emerging trends in biomedicine and health technology innovation: addressing the global challenge of Alzheimer’s. 2013.Google Scholar
  4. 4.
    Andrieu S, Coley N, Aisen P, et al. Methodological issues in primary prevention trials for neurodegenerative dementia. J. Alzheimers Dis. 2009;16:235–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Carrillo MC, Brashear HR, Logovinsky V, et al. Can we prevent Alzheimer’s disease? Secondary «prevention» trials in Alzheimer’s disease. Alzheimers Dement. 2013;9:123–31 e1.PubMedGoogle Scholar
  6. 6.
    Carrillo MC, Vellas B. New and different approaches needed for the design and execution of Alzheimer’s clinical trials. Alzheimers Dement. 2013;9:436–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Doody RS, Cole PE, Miller DS, et al. Global issues in drug development for Alzheimer’s disease. Alzheimers Dement. 2011;7:197–207.PubMedCrossRefGoogle Scholar
  8. 8.
    Mohs RC, Kawas C, Carrillo MC. Optimal design of clinical trials for drugs designed to slow the course of Alzheimer’s disease. Alzheimers Dement. 2006;2:131–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Vellas B, Carrillo MC, Sampaio C, et al. Designing drug trials for Alzheimer’s disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD Task Force. Alzheimers Dement. 2013;9:438–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Vellas B, Hampel H, Rouge–Bugat ME, et al. Alzheimer’s disease therapeutic trials: EU/US Task Force report on recruitment, retention, and methodology. J. Nutr. Health Aging. 2012;16:339–45.PubMedCrossRefGoogle Scholar
  11. 11.
    Khachaturian ZS. The paradox of reearch on dementia–Alzheimer’s disease. J. Prev. Alzheimers Dis. 2015;4:1–3.Google Scholar
  12. 12.
    Pazzagli A, Pepeu G. Amnesic properties of scopolamine and brain acetylcholine in the rat. Int. J. Neuropharmacol. 1965;4:291–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Bohdanecky Z, Jarvik ME, Carley JL. Differential impairment of delayed matching in monkeys by scopolamine and scopolamine methylbromide. Psychopharmacologia. 1967;11:293–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Deutsch JA. The cholinergic synapse and the site of memory. Science. 1971;174:788–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Shute CC, Lewis PR. The ascending cholinergic reticular system: neocortical, olfactory and subcortical projections. Brain. 1967;90:497–520.PubMedCrossRefGoogle Scholar
  16. 16.
    Drachman DA, Leavitt J. Human memory and the cholinergic system. A relationship to aging? Arch Neurol. 1974;30:113–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Bowen DM, Smith CB, White P, Davison AN. Neurotransmitter–related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain. 1976;99(3):459–96.PubMedCrossRefGoogle Scholar
  18. 18.
    Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet. 1976;2:1403.PubMedCrossRefGoogle Scholar
  19. 19.
    Bartus RT, Johnson HR. Short–term memory in the rhesus monkey: disruption from the anti–cholinergic scopolamine. Pharmacol. Biochem. Behav. 1976;5:39–46.PubMedCrossRefGoogle Scholar
  20. 20.
    Bartus RT. Physostigmine and recent memory: effects in young and aged nonhuman primates. Science. 1979;206:1087–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Bartus RT, Dean RL 3rd, Beer B, et al. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982;217:408–14.PubMedCrossRefGoogle Scholar
  22. 22.
    Mesulam MM, Van Hoesen GW. Acetylcholinesterase–rich projections from the basal forebrain of the rhesus monkey to neocortex. Brain Res. 1976;109:152–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Whitehouse PJ, Price DL, Struble RG, et al. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;215:1237–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Coyle JT, Price DL, DeLong MR. Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science. 1983;219:1184–90.PubMedCrossRefGoogle Scholar
  25. 25.
    Francis PT, Palmer AM, Sims NR, et al. Neurochemical studies of early–onset Alzheimer’s disease. Possible influence on treatment. The New England journal of medicine. 1985;313:7–11.PubMedCrossRefGoogle Scholar
  26. 26.
    Perry EK, Tomlinson BE, Blessed G, et al. Neuropathological and biochemical observations on the noradrenergic system in Alzheimer’s disease. J. Neurol. Sci. 1981;51:279–87.PubMedCrossRefGoogle Scholar
  27. 27.
    Summers WK, Majovski LV, Marsh GM, et al. Oral tetrahydroaminoacridine in long–term treatment of senile dementia, Alzheimer type. The New England journal of medicine. 1986;315:1241–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Mesulam M, Shaw P, Mash D, et al. Cholinergic nucleus basalis tauopathy emerges early in the aging–MCI–AD continuum. Ann. Neurol. 2004;55:815–28.PubMedCrossRefGoogle Scholar
  29. 29.
    Mufson EJ, Counts SE, Perez SE, et al. Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Rev. Neurother. 2008;8:1703–18.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Mesulam M. The cholinergic lesion of Alzheimer’s disease: pivotal factor or side show? Learn. Mem. 2004;11:43–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Geula C, Mesulam M–M. Cholinergic systems in Alzheimer’s disease. In: Terry RD, Katzman R, Bick KL, Sisodia SS, editors. Alzheimer Disease. 2nd ed. Philadelphia: Lippincott, Williams & Wilkins; 1999. p. 269–92.Google Scholar
  32. 32.
    Francis PT, Palmer AM, Snape M, et al. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J. Neurol. Neurosurg. Psychiatry. 1999;66:137–47.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Bartus RT, Dean RL, Pontecorvo MJ, et al. The cholinergic hypothesis: a historical overview, current perspective, and future directions. Ann. N Y Acad. Sci. 1985;444:332–58.PubMedCrossRefGoogle Scholar
  34. 34.
    Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug–development pipeline: few candidates, frequent failures. Alzheimers Res. Ther. 2014;6:37.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late–stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J. Intern. Med. 2014;275:251–83.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Rogalski E, Sridhar J, Rader B, et al. Aphasic variant of Alzheimer disease: Clinical, anatomic, and genetic features. Neurology. 2016;87:1337–1443.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Hampel H, O’Bryant SE, Castrillo JI, Ritchie C, Rojkova R, Broich K, et al. Precision Medicine–The golden gate for detection, treatment, and prevention of Alzheimer’s disease. J. Prev. Alzheimers Dis. 2016;3:243–259.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Hampel H, O’Bryant SE, Durrleman S, et al. A precision medicine initiative for Alzheimer’s disease–the road ahead to biomarker–guided integrative disease modeling. Climacteric. 2017;20: 107–118.Google Scholar
  39. 39.
    Giacobini E, Gold G. Alzheimer disease therapy––moving from amyloid–beta to tau. Nat. Rev. Neurol. 2013;9:677–86.PubMedCrossRefGoogle Scholar
  40. 40.
    Mesulam MM. Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer’s disease. J. Comp. Neurol. 2013;521:4124–44.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Mesulam MM, Mufson EJ. Neural inputs into the nucleus basalis of the substantia innominata (Ch4) in the rhesus monkey. Brain. 1984;107:253–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Mesulam M. Cholinergic aspects of aging and Alzheimer’s disease. Biol. Psychiatry. 2012;71:760–1.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Schliebs R, Arendt T. The cholinergic system in aging and neuronal degeneration. Behav. Brain Res. 2011;221:555–63.PubMedCrossRefGoogle Scholar
  44. 44.
    Grothe M, Zaborszky L, Atienza M, et al. Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer’s disease. Cereb. Cortex. 2010;20:1685–95.PubMedCrossRefGoogle Scholar
  45. 45.
    Grothe M, Heinsen H, Teipel S. Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer’s disease. Neurobiol. Aging. 2013;34:1210–20.PubMedCrossRefGoogle Scholar
  46. 46.
    Beach TG, Kuo YM, Spiegel K, et al. The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease. J. Neuropathol. Exp. Neurol. 2000;59:308–13.PubMedCrossRefGoogle Scholar
  47. 47.
    Potter PE, Rauschkolb PK, Pandya Y, et al. Pre–and post–synaptic cortical cholinergic deficits are proportional to amyloid plaque presence and density at preclinical stages of Alzheimer’s disease. Acta Neuropathol. 2011;122:49–60.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Beach TG, Honer WG, Hughes LH. Cholinergic fibre loss associated with diffuse plaques in the non–demented elderly: the preclinical stage of Alzheimer’s disease? Acta Neuropathol. 1997;93:146–53.PubMedCrossRefGoogle Scholar
  49. 49.
    Kerbler GM, Fripp J, Rowe CC, et al. Basal forebrain atrophy correlates with amyloid beta burden in Alzheimer’s disease. Neuroimage Clin. 2015;7:105–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Grothe MJ, Heinsen H, Amaro E, Jr., et al. Cognitive Correlates of Basal Forebrain Atrophy and Associated Cortical Hypometabolism in Mild Cognitive Impairment. Cereb. Cortex. 2016;26:2411–26.PubMedCrossRefGoogle Scholar
  51. 51.
    Corkin S. Acetylcholine, aging and Alzheimer’s disease. Trends in Neurosciences. 1981;4:287–90.CrossRefGoogle Scholar
  52. 52.
    Gerretsen P, Pollock BG. Drugs with anticholinergic properties: a current perspective on use and safety. Expert Opin. Drug Saf. 2011;10:751–65.PubMedCrossRefGoogle Scholar
  53. 53.
    Lim YY, Maruff P, Schindler R, et al. Disruption of cholinergic neurotransmission exacerbates Abeta–related cognitive impairment in preclinical Alzheimer’s disease. Neurobiol. Aging. 2015;36:2709–15.PubMedCrossRefGoogle Scholar
  54. 54.
    Giacobini E, DeSarno P, McIlhany M, et al. The cholinergic receptors system in the frontal lobe of Alzheimer patients. In: Clementi F, Gotti C, Sher E, editors. Nicotinic Acetylcholine Receptors in the Nervous System. 25. Berlin, Heidelberg: Springer; 1988. p. 367–78.Google Scholar
  55. 55.
    Giacobini E. The cholinergic system in Alzheimer disease. Prog. Brain Res. 1990;84:321–32.PubMedCrossRefGoogle Scholar
  56. 56.
    Fisher A. Cholinergic modulation of amyloid precursor protein processing with emphasis on M1 muscarinic receptor: perspectives and challenges in treatment of Alzheimer’s disease. J. Neurochem. 2012;120 Suppl 1:22–33.Google Scholar
  57. 57.
    Fisher A, Bezprozvanny I, Wu L, et al. AF710B, a Novel M1/sigma1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s Disease. Neurodegener. Dis. 2016;16:95–110.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Hall H, Iulita MF, Ducatenzeiler A, et al. Pro–cognitive and anti–inflammatory effects of AF710B, a mixed M1 muscarinic/sigma–1 receptor agonist, in the McGill–R–Thy1–APP rat model of human AD–like amyloid pathology. Alzheimers Dement. 2016;12:P1019.Google Scholar
  59. 59.
    Nordberg A, Winblad B. Reduced number of [3H]nicotine and [3H] acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci. Lett. 1986;72:115–9.PubMedCrossRefGoogle Scholar
  60. 60.
    DeSarno P, Giacobini E, McIlhany M, et al. Nicotinic receptors in human CNS: a biopsy study. In: Agnoli A, editor. 2nd Int Symp on Senile Dementias Montrouge, France: John Libbey Eurotext, Ltd.; 1988. p. 329–34.Google Scholar
  61. 61.
    Kadir A, Almkvist O, Wall A, et al. PET imaging of cortical 11C–nicotine binding correlates with the cognitive function of attention in Alzheimer’s disease. Psychopharmacology (Berl). 2006;188:509–20.PubMedCrossRefGoogle Scholar
  62. 62.
    Parri HR, Hernandez CM, Dineley KT. Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer’s disease. Biochem. Pharmacol. 2011;82:931–42.PubMedCrossRefGoogle Scholar
  63. 63.
    Deardorff WJ, Shobassy A, Grossberg GT. Safety and clinical effects of EVP–6124 in subjects with Alzheimer’s disease currently or previously receiving an acetylcholinesterase inhibitor medication. Expert Rev Neurother. 2015;15:7–17.PubMedCrossRefGoogle Scholar
  64. 64.
    Teipel SJ, Flatz WH, Heinsen H, et al. Measurement of basal forebrain atrophy in Alzheimer’s disease using MRI. Brain. 2005;128:2626–44.PubMedCrossRefGoogle Scholar
  65. 65.
    Teipel SJ, Meindl T, Grinberg L, et al. The cholinergic system in mild cognitive impairment and Alzheimer’s disease: an in vivo MRI and DTI study. Hum. Brain Mapp. 2011;32:1349–62.PubMedCrossRefGoogle Scholar
  66. 66.
    Schmitz TW, Nathan Spreng R, et al. Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology. Nat. Commun. 2016;7:13249.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Grothe M, Heinsen H, Teipel SJ. Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer’s disease. Biol. Psychiatry. 2012;71:805–13.PubMedCrossRefGoogle Scholar
  68. 68.
    Hall AM, Moore RY, Lopez OL, et al. Basal forebrain atrophy is a presymptomatic marker for Alzheimer’s disease. Alzheimers Dement. 2008;4:271–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Kilimann I, Grothe M, Heinsen H, et al. Subregional basal forebrain atrophy in Alzheimer’s disease: a multicenter study. J. Alzheimers Dis. 2014;40:687–700.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Grothe MJ, Ewers M, Krause B, et al. Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects. Alzheimers Dement. 2014;10:S344–53.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Cavedo E, Dubois B, Colliot O, et al. Reduced Regional Cortical Thickness Rate of Change in Donepezil–Treated Subjects With Suspected Prodromal Alzheimer’s Disease. J. Clin. Psychiatry. 2016;77: e1631–e1638.Google Scholar
  72. 72.
    Dubois B, Chupin M, Hampel H, et al. Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer’s disease. Alzheimers Dement. 2015;11:1041–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Cavedo E, Grothe M, Colliot O, et al. Reduced basal forebrain atrophy progression in a randomized Donepezil trial in prodromal Alzheimer’s disease. Scientific Reports. 2017;7:11706.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    in t’Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. The New England journal of medicine. 2001;345:1515–21.CrossRefGoogle Scholar
  75. 75.
    Zandi PP, Anthony JC, Hayden KM, et al. Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology. 2002;59:880–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Cuello AC. Effects of trophic factors on the CNS cholinergic phenotype. Prog. Brain Res. 1996;109:347–58.PubMedCrossRefGoogle Scholar
  77. 77.
    Hefti F. Neurotrophic factor therapy for nervous system degenerative diseases. J. Neurobiol. 1994;25:1418–35.PubMedCrossRefGoogle Scholar
  78. 78.
    Olson L, Nordberg A, von Holst H, et al. Nerve growth factor affects 11C–nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (case report). J. Neural. Transm. Park. Dis. Dement. Sect. 1992;4:79–95.PubMedCrossRefGoogle Scholar
  79. 79.
    Seiger A, Nordberg A, von Holst H, et al. Intracranial infusion of purified nerve growth factor to an Alzheimer patient: the first attempt of a possible future treatment strategy. Behav. Brain Res. 1993;57:255–61.PubMedCrossRefGoogle Scholar
  80. 80.
    Cuello AC, Thoenen H. The Pharmacology of Neurotrophic Factors. In: Cuello C, Collier B, editors. Pharmacologic Sciences: Perspectives for Research and Therapy in the Late 1990s. Basel: Birkhauser–Verlag; 1995.Google Scholar
  81. 81.
    Eriksdotter Jonhagen M, Nordberg A, Amberla K, et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 1998;9:246–57.PubMedCrossRefGoogle Scholar
  82. 82.
    Eyjolfsdottir H, Eriksdotter M, Linderoth B, et al. Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer’s disease patients: application of a second–generation encapsulated cell biodelivery device. Alzheimers Res. Ther. 2016;8:30.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Tuszynski MH, Thal L, Pay M, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 2005;11:551–5.PubMedCrossRefGoogle Scholar
  84. 84.
    Tuszynski MH, Yang JH, Barba D, et al. Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurol. 2015;72:1139–47.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Bruno MA, Cuello AC. Activity–dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc. Natl. Acad. Sci. U S A. 2006;103:6735–40.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Bruno MA, Leon WC, Fragoso G, et al. Amyloid beta–induced nerve growth factor dysmetabolism in Alzheimer disease. J. Neuropathol. Exp. Neurol. 2009;68:857–69.PubMedCrossRefGoogle Scholar
  87. 87.
    Iulita MF, Do Carmo S, Ower AK, et al. Nerve growth factor metabolic dysfunction in Down’s syndrome brains. Brain. 2014;137:860–72.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Casanova MF, Walker LC, Whitehouse PJ, et al. Abnormalities of the nucleus basalis in Down’s syndrome. Ann. Neurol. 1985;18:310–3.PubMedCrossRefGoogle Scholar
  89. 89.
    Wilcock DM. Neuroinflammation in the aging down syndrome brain; lessons from Alzheimer’s disease. Curr. Gerontol. Geriatr. Res. 2012;2012:170276.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Iulita MF, Ower AK, Barone C, et al. An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation. Alzheimers Dement. 2016;12:1132–1148.PubMedCrossRefGoogle Scholar
  91. 91.
    Allard S, Leon WC, Pakavathkumar P, et al. Impact of the NGF maturation and degradation pathway on the cortical cholinergic system phenotype. J. Neurosci. 2012;32:2002–12.PubMedCrossRefGoogle Scholar
  92. 92.
    Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild–to–moderate Alzheimer’s disease. The New England journal of medicine. 2014;370:311–21.PubMedCrossRefGoogle Scholar
  93. 93.
    Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild–to–moderate Alzheimer’s disease. The New England journal of medicine. 2014;370:322–33.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Fredrickson A, Snyder PJ, Cromer J, et al. The use of effect sizes to characterize the nature of cognitive change in psychopharmacological studies: an example with scopolamine. Hum. Psychopharmacol. 2008;23:425–36.PubMedCrossRefGoogle Scholar
  95. 95.
    Papp KV, Snyder PJ, Maruff P, et al. Detecting subtle changes in visuospatial executive function and learning in the amnestic variant of mild cognitive impairment. PLoS One. 2011;6:e21688.CrossRefGoogle Scholar
  96. 96.
    Thomas E, Snyder PJ, Pietrzak RH, et al. Specific impairments in visuospatial working and short–term memory following low–dose scopolamine challenge in healthy older adults. Neuropsychologia. 2008;46:2476–84.PubMedCrossRefGoogle Scholar
  97. 97.
    Snyder PJ, Lim YY, Schindler R, et al. Microdosing of scopolamine as a «cognitive stress test»: rationale and test of a very low dose in an at–risk cohort of older adults. Alzheimers Dement. 2014;10:262–7.PubMedCrossRefGoogle Scholar
  98. 98.
    Courtney C, Farrell D, Gray R, et al. Long–term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double–blind trial. Lancet. 2004;363:2105–15.PubMedCrossRefGoogle Scholar
  99. 99.
    Doody RS, Dunn JK, Clark CM, et al. Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 2001;12:295–300.PubMedCrossRefGoogle Scholar
  100. 100.
    Farlow MR, Lilly ML, Group EBS. Rivastigmine: an open–label, observational study of safety and effectiveness in treating patients with Alzheimer’s disease for up to 5 years. BMC Geriatr. 2005;5:3.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Rogers SL, Doody RS, Pratt RD, et al. Long–term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open–label study. Eur. Neuropsychopharmacol. 2000;10:195–203.PubMedCrossRefGoogle Scholar
  102. 102.
    Doraiswamy PM, Krishnan KR, Anand R, et al. Long–term effects of rivastigmine in moderately severe Alzheimer’s disease: does early initiation of therapy offer sustained benefits? Prog. Neuropsychopharmacol Biol. Psychiatry. 2002;26:705–12.PubMedCrossRefGoogle Scholar
  103. 103.
    Foster NL, Petersen RC, Gracon SI, et al. An enriched–population, doubleblind, placebo–controlled, crossover study of tacrine and lecithin in Alzheimer’s disease. The Tacrine 970–6 Study Group. Dementia. 1996;7:260–6.Google Scholar
  104. 104.
    Davis KL, Mohs RC, Marin D, et al. Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA. 1999;281:1401–6.PubMedCrossRefGoogle Scholar
  105. 105.
    Schredl M, Weber B, Leins ML, et al. Donepezil–induced REM sleep augmentation enhances memory performance in elderly, healthy persons. Exp. Gerontol. 2001;36:353–61.PubMedCrossRefGoogle Scholar
  106. 106.
    Davis B, Sadik K. Circadian cholinergic rhythms: implications for cholinesterase inhibitor therapy. Dement. Geriatr. Cogn. Disord. 2006;21:120–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Giacobini E, Spiegel R, Enz A, et al. Inhibition of acetyl–and butyrylcholinesterase in the cerebrospinal fluid of patients with Alzheimer’s disease by rivastigmine: correlation with cognitive benefit. J. Neural. Transm. (Vienna). 2002;109:1053–65.PubMedCrossRefGoogle Scholar
  108. 108.
    Almkvist O, Darreh–Shori T, Stefanova E, et al. Preserved cognitive function after 12 months of treatment with rivastigmine in mild Alzheimer’s disease in comparison with untreated AD and MCI patients. Eur. J. Neurol. 2004;11:253–61.PubMedCrossRefGoogle Scholar
  109. 109.
    Rountree SD, Atri A, Lopez OL, et al. Effectiveness of antidementia drugs in delaying Alzheimer’s disease progression. Alzheimers Dement. 2013;9:338–45.PubMedCrossRefGoogle Scholar
  110. 110.
    Selkoe DJ. SnapShot: pathobiology of Alzheimer’s disease. Cell. 2013;154:468–e1.PubMedCrossRefGoogle Scholar
  111. 111.
    Castro A, Martinez A. Targeting beta–amyloid pathogenesis through acetylcholinesterase inhibitors. Curr. Pharm. Des. 2006;12:4377–87.PubMedCrossRefGoogle Scholar
  112. 112.
    Hampel H, Mesulam MM, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain. 2018 Jul 1;141:1917–1933.PubMedCrossRefGoogle Scholar
  113. 113.
    Gauthier S, Herrmann N, Rosa–Neto P. Optimal use of cholinergic drugs in Alzheimer’s disease. Brain. 2018. in pressGoogle Scholar
  114. 114.
    Hampel H, Cavedo E, Vergallo A. Dawn of Alzheimer Precision Pharmacology and the Renaissance of Cholinergic drugs. Brain. 2018. in pressGoogle Scholar
  115. 115.
    Petersen RC, Oscar Lopez O, Armstrong MJ, et al. Practice guideline update summary: Mild cognitive impairment Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2018;90:126–135.PubMedCrossRefGoogle Scholar

Copyright information

© Serdi and Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Harald Hampel
    • 1
    • 2
    • 3
    • 4
  • M.-M. Mesulam
    • 5
  • A. C. Cuello
    • 6
  • A. S. Khachaturian
    • 7
  • A. Vergallo
    • 1
    • 2
    • 3
    • 4
  • M. R. Farlow
    • 8
  • P. J. Snyder
    • 9
  • E. Giacobini
    • 10
  • Z. S. Khachaturian
    • 11
  • Cholinergic System Working Group, and for the Alzheimer Precision Medicine Initiative (APMI)
  1. 1.AXA Research Fund & Sorbonne University ChairSorbonne University, Department of Neurology, Institute of Memory and Alzheimer’s Disease (IM2A), Brain & Spine Institute (ICM), François Lhermitte Building, Pitié-Salpêtrière HospitalParis CEDEX 13France
  2. 2.Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l’hôpitalParisFrance
  3. 3.Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225ParisFrance
  4. 4.Institute of Memory and Alzheimer’s Disease (IM2A), Department of Neurology, Pitié-Salpêtrière HospitalAP-HPParisFrance
  5. 5.Cognitive Neurology and Alzheimer’s Disease CenterNorthwestern University Feinberg School of MedicineChicagoUSA
  6. 6.Department of Pharmacology and Therapeutics, Department of Neurology and Neurosurgery, Department of Anatomy and Cell BiologyMcGill UniversityMontrealCanada
  7. 7.Executive Vice-PresidentThe Campaign to Prevent Alzheimer’s Disease by 2020PotomacUSA
  8. 8.Department of NeurologyIndiana University School of MedicineIndianapolisUSA
  9. 9.Vice-President for Research and Economic DevelopmentUniversity of Rhode IslandKingstonUSA
  10. 10.Department of Internal Medicine, Rehabilitation and Geriatrics, University of Geneva Hospitals, Faculty of MedicineUniversity of GenevaGenevaSwitzerland
  11. 11.The Campaign to Prevent Alzheimer’s Disease by 2020 (PAD2020)PotomacUSA

Personalised recommendations