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

  • Harald HampelEmail author
  • 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)
Point of View


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


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Copyright information

© Serdi and Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Harald Hampel
    • 1
    • 2
    • 3
    • 4
    Email author
  • 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.The 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

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