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

J Prev Alzheimers Dis. 2019;6(1):2-15. doi: 10.14283/jpad.2018.43.


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.

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

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging / physiology
  • Alzheimer Disease* / complications
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / pathology
  • Alzheimer Disease* / physiopathology
  • Brain / pathology
  • Cholinergic Agents / therapeutic use*
  • Cholinergic Neurons / pathology*
  • Cholinergic Neurons / physiology*
  • Cognitive Dysfunction / complications
  • Cognitive Dysfunction / drug therapy
  • Cognitive Dysfunction / physiopathology
  • Dementia / pathology
  • Dementia / physiopathology
  • Humans
  • Translational Research, Biomedical*


  • Cholinergic Agents