Long-term stabilizing effect of cholinesterase inhibitors in the therapy of Alzheimer’ disease

  • E. Giacobini
Part of the Journal of Neural Transmission. Supplementa book series (NEURAL SUPPL, volume 62)


During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) resulted into three drugs being registered for the first time in USA and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6 months to one year period of treatment as compared to placebo. Additional drug effects are slowing cognitive deterioration and improving behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and direct cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission experimental or pathological (AD) leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. In order to explain the long-term effect of ChEI, a mechanism based on ~amyloid metabolism, is postulated. Evidence for such an effect is available at experimental as well as at clinical level. Does cholinergic stabilization imply slowing down disability or delaying disease progression?


Alzheimer Disease Amyloid Precursor Protein Cholinesterase Inhibitor Alzheimer Disease Patient ChEI Treatment 
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  1. Alvarez A (1997) Acetylcholinesterase promotes the aggregation of amyloid B-peptide fragments by forming a complex with the growing fibrils. J Mol Bioi 272: 348–361Google Scholar
  2. Anand R, Hartman R, Messina J (1998) Long-term treatment with rivastigmine continue to provide benefits for up to one year. Fifth Int Geneva/Springfield Symposium on Advances in Alzheimer Therapy, Geneva, Abstracts, p 18Google Scholar
  3. Bernhardt T, Woelk H (2000) Metrifonate demonstrates sustained improvement in cognition and global functioning in a 12-month, double blind placebo-controlled trial. Eur Neurol Soc Meeting, Jerusalem, p 36Google Scholar
  4. FarlowM (2000) New approaches in asssessing delay of progression of AD. Symp Pivotal Research, World Alzheimer Congress, Washington D.C. Abstracts, pp 10–11Google Scholar
  5. Giacobini E (1996) Cholinesterase inhibitors do more than inhibit cholinesterase. In: Becker R, Giacobini E (eds) Alzheimer disease: from molecular biology to therapy. Birkhiiuser, Boston, pp 187–204Google Scholar
  6. Giacobini E (1998) Cholinesterase inhibitors for Alzheimer’s disease therapy, from tacrine to future applications. Neurochem Int 32: 413–419PubMedCrossRefGoogle Scholar
  7. Giacobini E (2000) Cholinesterase inhibitors: from the calabar bean to Alzheimetherapy. In: Giacobini E (ed) Cholinesterase and cholinesterase inhibitors. From molecular biology to therapy. Martin Dunitz, London, pp 181–22Google Scholar
  8. Giacobini E (2001) Is anti-cholinesterase therapy of Alzheimer’s disease delaying progression? Aging Clin Exp Res 13: 247–254Google Scholar
  9. Giacobini E, Gold G, Michel J-P (2001) Vaccination:traitement de demain pour lamaladie d’ Alzheimer? Med Hyg 59: 103–107Google Scholar
  10. Haroutunian V, Wallace WC, Greig N (2000) Induction, secretion and pharmacological regulation of beta-APP in animal model systems. Sixth Int Stockholm/Springfield Symp, Adv in Alzheimer Therapy. Abstracts, p 81Google Scholar
  11. Inestrosa N, Alvarez A, Perez CA (1996) Acetylcholinesterase accellerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 16: 881–891PubMedCrossRefGoogle Scholar
  12. Inestrosa NC, Alvarez A, Reyes A, De Ferrari GV (2000) Acetylcholinesterase-amyloidpeptide interaction and Wnt signaling involvment in A-beta neurotoxicity. Acta Neurol Scand [Suppl 176]: 53–59Google Scholar
  13. Lahiri DK, Farlow MR, Hintz N, Utsuki T, Greig NH (2000) Cholinesterase inhibitors, beta-amyloid precursor protein and amyloid beta-peptides in Alzheimer’s disease. Acta Neurol Scand [Suppl 176]:60–67Google Scholar
  14. Matthews HP (2000) Donepezil in Alzheimer’s disease: eighteenmonth results from Southampton memory clinic. Int J Ger Psych 15: 713–720CrossRefGoogle Scholar
  15. Mori F, Lai CC, Fusi F, Giacobini E (1995) Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neurol Rep 6: 633–6Google Scholar
  16. Nitsch RM (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258: 304–307PubMedCrossRefGoogle Scholar
  17. Pakaski M, Rakonczay Z, Kasa P (2001) Reversible or irreversible cholinesterase inhibitors cause changes in neuronal amyloid percursor processing and protein kinase C level in vitro. Neurochem Int 38: 219–226PubMedCrossRefGoogle Scholar
  18. Racchi M, Schmidt B, Koenig G (1999) Treatment with metrifonate promotes soluble amyloid precursor protein release from SH-SY5Y neuroblastoma cells. Alz Dis Assoc Disord 13: 679–688Google Scholar
  19. Raskind MA, Peskind ER, Wessel T (2000) Galantamine in AD. A sixth month randomized, placebo-controlled trial with a 6-month extension. Neurology 54: 2261–2268Google Scholar
  20. Rogers SL (2000) Long-term efficacy and safety of donezepil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open-label study. Eur Neuropsychopharm 10: 195–203CrossRefGoogle Scholar
  21. Small DH, Sbema G, Li QX et al (1998) The beta-amyloid protein influences acetylcholinesterasye expression, assembly and glycosylation. 6th Int Conf Alzheimer’s Disease, Amsterdam. AbstractsGoogle Scholar
  22. Suh Y-H, Chong Yh, Kim S-H et al (1996) Molecular physiology, biochemistry and pharmacology of Alzheimer’s amyloid precursor protein (APP). Ann NY Acad 786:169–183CrossRefGoogle Scholar
  23. Wallace WC, Bragin V, Robakis NK (1991) Increased byosynthesis of Alzheimer amyloid precursor protein in the cerebral cortex of rats with lesions of the nucleus basalis Meynert. Mol Brain Res 10: 173–178PubMedCrossRefGoogle Scholar

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© Springer-Verlag Wien 2002

Authors and Affiliations

  • E. Giacobini
    • 1
  1. 1.Department of GeriatricsUniversity Hospitals of Geneva, University of Geneva, Medical SchoolThonexSwitzerland

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