Revisiting the cholinergic hypothesis in Alzheimer's disease: Emerging evidence from translational and clinical research

Harald Hampel*, Marsel M. Mesulam, A. Claudio Cuello, Ara S. Khachaturian, Martin R. Farlow, Peter J. Snyder, Ezio Giacobini, Zaven S. Khachaturian

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Scientific evidence collected over the past four decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease (AD) 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 is one of several interacting systems failures that contribute to AD pathogenesis.

Original languageEnglish (US)
JournalAlzheimer's and Dementia
StateAccepted/In press - Jan 1 2017


  • Alzheimer's disease
  • Basal forebrain cholinergic system atrophy
  • Cholinergic system
  • Cholinesterase inhibitors
  • Nerve growth factor
  • Nucleus basalis of Meynert (NbM) degeneration

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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