title: Cholinesterase inhibition: is there evidence for disease-modifying effects?
abstract: BACKGROUND
  Cholinesterase inhibitors are broadly established as first-line symptomatic therapy for Alzheimer's disease (AD). Symptomatic effects are mediated by the inhibition of acetyl- and/or butyryl-cholinesterase (AChE and/or BuChE) - the enzymes that degrade acetylcholine (ACh) in the synapse. However, ACh is also found outside the synapse ('extracellular ACh') where, among other activities, it plays a role in controlling inflammation and might impact on pathological changes. OBJECTIVE/SCOPE: New data and clinical findings are reviewed and discussed to build a preliminary case for possible disease-modifying effects of cholinesterase inhibition.
  
  
  RESULTS
  Trials seeking to demonstrate disease-modifying effects in subjects with mild cognitive impairment failed to reach their primary endpoints, but these failures might relate to aspects of trial methods and analyses. A re-analysis of one of these trials, using a more sensitive model controlling for factors that predict progression to AD, showed a significant delay in progression to AD with dual cholinesterase inhibition over 3 to 4 years. Taken with other evidence, it is plausible that cholinesterase inhibition might contribute to disease modification. The detection of putative disease-modifying effects may be most easily implemented in certain patient subpopulations, and genotyping studies suggest a particular role for BuChE.
  
  
  CONCLUSIONS
  Long-term inhibition of BuChE might be especially important when exploring any disease-modifying effects of cholinesterase inhibitors. Elucidation of the mechanisms involved could provide insights leading to the development of new treatments that modify the development and progression of AD.
authors.affiliation: Clinical Neuroscience Centre, University of Hull, Hull HU6 7RX, UK. M.Shanks@hull.ac.uk
authors.forename: Michael
authors.initials: M
authors.lastname: Shanks
authors.forename: Miia
authors.initials: M
authors.lastname: Kivipelto
authors.forename: Roger
authors.initials: R
authors.lastname: Bullock
authors.forename: Roger
authors.initials: R
authors.lastname: Lane
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D006801:Humans
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase