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To treat or not to treat? A meta-analysis of the use of cholinesterase inhibitors in mild cognitive impairment for delaying progression to Alzheimer’s disease

  • Breno Satler Diniz
  • Jony Arrais PintoJr
  • Maria Luiza Cavichioli Gonzaga
  • Fabiana Meira Guimarães
  • Wagner Farid Gattaz
  • Orestes Vicente Forlenza
ORIGINAL PAPER

Abstract

Background

Individual randomized clinical trials (RCTs) with cholinesterase inhibitors (ChEIs) aiming to delay the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) have not found significant benefit of their use for this purpose. The objective of this study is to meta-analyze the RCTs conducted with ChEIs in order to assess whether pooled analysis could show the benefit of these drugs in delaying the progression from MCI to AD.

Methods

We searched for references of published and unpublished studies on electronic databases (Medline, Embase, Web of Science, and Clinical Trial Database Registry, particularly the Clinicaltrials.gov—http://www.clinicaltrials.gov). We retrieved 173 references, which yielded three references for data extraction. A total of 3.574 subjects from four RCTs were included in the meta-analysis. Among 1,784 subjects allocated in the ChEI-treatment group, 275 (15.4%) progressed to AD/dementia, as opposed to 366 (20.4%) out of 1,790 subjects in the placebo group. The relative risk (RR) for progression to AD/dementia in the ChEI-treated group was 0.75 [CI95% 0.66–0.87], z = −3.89, P < 0.001. The patients on the ChEI group had a significantly higher all-cause dropout risk than the patients on the placebo group (RR = 1.36 CI95% [1.24–1.49]; z = 6.59, P < 0.001). The RR for serious adverse events (SAE) in the ChEI-treated group showed no significantly statistical difference from the placebo group (RR = 0.95 [CI95% 0.83–1.09], z = −0.72, P = 0.47). The subjects in the ChEI-treated group had a marginally, non-significant, higher risk of death due to any cause than those in the placebo-treated group (RR = 1.04, CI95% 0.63–1.70, z = 0.16, P = 0.86).

Conclusion

The long-term use of ChEIs in subjects with MCI may attenuate the risk of progression to AD/dementia. This finding may have a significant impact on public health and pharmaco-economic policies.

Keywords

mild cognitive impairment treatment disease-modifying therapies Alzheimer’s disease progression 

Notes

Conflict of interest

Dr. Gattaz has received research support and speakership honoraria from AstraZeneca, Bristol Myers-Squibb, Eli Lilly, and Janssen-Cilag.

References

  1. 1.
    [No author listed] (2004) Efficacy and safety of rivastigmine in patients with mild cognitive impairment. NCT00134953. Available on-line on http://www.clinicaltrials.gov/ct2/show/NCT00134953. Accessed 27 Oct 2008
  2. 2.
    [No author’s listed]. (2007) A randomized double blind parallel, placebo-controlled trial to examine the efficacy of oral donepezil (5 mg qd for 6 weeks) after single dose and steady state therapy (2 and 6 weeks) in subjects with mild cognitive impairment. NCT00483028. Available on-line on http://clinicaltrials.gov/ct2/show/NCT00483028. Accessed 27 Oct 2008
  3. 3.
    [No authors listed] (2004) Cognitive enhancers explored with PET imaging. NCT 00042172. Available on-line http://clinicaltrials.gov/ct2/show/NCT00042172. Accessed 27 Oct 2008
  4. 4.
    Ames D, Petersen RC, Knopman DS, Visser PJ, Brodaty H, Gauthier S (2006) Is mild cognitive impairment a clinically useful concept? Int Psychogeriatr 18:393–414CrossRefGoogle Scholar
  5. 5.
    Anita M (2007) A one-year, multicenter, randomized, double-blind, placebo controlled evaluation of the efficacy and safety of donepezil hydrochloride in subjects with mild cognitive impairment. NCT00293176. Available on line http://clinicaltrials.gov/ct2/show/NCT00293176. Accessed 27 Oct 2008
  6. 6.
    Bäckman L, Small BJ, Fratiglioni L (2001) Stability of the preclinical episodic memory deficit in Alzheimer’s disease. Brain 124:96–102PubMedCrossRefGoogle Scholar
  7. 7.
    Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 3:186–191CrossRefGoogle Scholar
  8. 8.
    Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe EA, Gandy SE, Greengard P (1992) Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proc Natl Acad Sci USA 89:10075–10078PubMedCrossRefGoogle Scholar
  9. 9.
    Cummings JL, Doody R, Clark C (2007) Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology 69:1622–1634PubMedCrossRefGoogle Scholar
  10. 10.
    Diniz BS, Pinto JA Jr, Forlenza OV (2008) Do CSF total tau, phosphorylated tau, and beta-amyloid 42 help to predict progression of mild cognitive impairment to Alzheimer’s disease? A systematic review and meta-analysis of the literature. World J Biol Psychiatry 9:172–182PubMedCrossRefGoogle Scholar
  11. 11.
    Doody R, Geldmacher D, Gordon B, Perdomo CA, Pratt RD, Donepezil Study Group (2001) Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol 58:427–433PubMedCrossRefGoogle Scholar
  12. 12.
    Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro OJ, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6:734–746PubMedCrossRefGoogle Scholar
  13. 13.
    Farias GG, Godoy JA, Hernandez F, Avila J, Fisher A, Inestrosa NC (2004) M1 muscarinic receptor activation protects neurons from beta-amyloid toxicity: a role for Wnt signaling pathway. Neurobiol Dis 17:337–348PubMedCrossRefGoogle Scholar
  14. 14.
    Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, del Ser T, Inzitari D, Orgogozo JM, Sauer H, Scheltens P, Scarpini E, Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R (2007) Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment: the InDDEx study. Lancet Neurol 6:501–512PubMedCrossRefGoogle Scholar
  15. 15.
    Forlenza OV, Chiu E (2008) Mild cognitive impairment: a concept ready to move on? Curr Opin Psychiatry 21:529–532PubMedCrossRefGoogle Scholar
  16. 16.
    Forlenza OV, Spink JM, Dayanandan R, Anderton BH, Olesen OF, Lovestone S (2000) Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3beta inhibition and in neurons. J Neural Transm 107:1201–1212PubMedCrossRefGoogle Scholar
  17. 17.
    Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5:228–234PubMedCrossRefGoogle Scholar
  18. 18.
    Hashimoto M, Kazui H, Matsumoto K, Nakano Y, Yasuda M, Mori E (2005) Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer’s disease? Am J Psychiatry 162:676–682PubMedCrossRefGoogle Scholar
  19. 19.
    Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104:1433–1439PubMedCrossRefGoogle Scholar
  20. 20.
    Jadad AR, Moore A, Carroll D, Jenkinson C, Reynolds JM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary. Controlled Clin Trials 17:1–12PubMedCrossRefGoogle Scholar
  21. 21.
    Koontz J, Baskys A (2005) Effects of galantamine on working memory and global functioning in patients with mild cognitive impairment: a double-blind placebo-controlled study. Am J Alzheimers Dis Other Demen 20:295–302PubMedCrossRefGoogle Scholar
  22. 22.
    Korf ESC, Wahlund LO, Visser PJ, Scheltens P (2004) Medial temporal lobe atrophy on MRI predicts dementia in patients with mild cognitive impairment. Neurology 63:94–100PubMedGoogle Scholar
  23. 23.
    Lanctôt KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, Einarson TR (2003) Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ 169:557–564PubMedGoogle Scholar
  24. 24.
    Leyhe T, Stransky E, Eschweiler GW, Buchkremer G, Laske C (2008) Increase of BDNF serum concentration during donepezil treatment of patients with early Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 258:124–128PubMedCrossRefGoogle Scholar
  25. 25.
    López-Pousa S, Turon-Estrada A, Garre-Olmo J, Pericot-Nierga I, Lozano-Gallego M, Vilalta-Franch M, Hernández-Ferràndiz M, Morante-Muñoz V, Isern-Vila A, Gelada-Batlle E, Majó-Llopart J (2005) Differential efficacy of treatment with cholinesterase inhibitors in patients with mild and moderate Alzheimer’s disease over a 6-month period. Dement Geriatr Cogn Disord 19:189–195PubMedCrossRefGoogle Scholar
  26. 26.
    Mahley RW, Weisgraber KH, Huang Y (2006) Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci USA 103:5644–5651PubMedCrossRefGoogle Scholar
  27. 27.
    Mendes CT, Mury FB, de Sá Moreira E, Alberto FL, Forlenza OV, Dias-Neto E, Gattaz WF (2008) Lithium reduces Gsk3b mRNA levels: implications for Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci [Epub ahead of print]Google Scholar
  28. 28.
    National Institute for Clinical Excellence (NICE) (2004) Management of depression in primary and secondary care. The British Psychological Society and Gaskel. LeicesterGoogle Scholar
  29. 29.
    Nitsch RM, Slack BE, Wurtman RJ, Growdon JH (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 28:304–307CrossRefGoogle Scholar
  30. 30.
    Petersen RC (2006) Conversion. Neurology 67(Suppl. 3):s12–s13PubMedGoogle Scholar
  31. 31.
    Petersen RC (2007) MCI treatment trials: failure or not? Lancet Neurol 6:473–475PubMedCrossRefGoogle Scholar
  32. 32.
    Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303–308PubMedCrossRefGoogle Scholar
  33. 33.
    Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, Alzheimer’s Disease Cooperative Study Group (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 352:2379–2388PubMedCrossRefGoogle Scholar
  34. 34.
    Pirttila T, Wilcock G, Truyen L, Damaraju CV (2004) Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease: multicenter trial. Eur J Neurol 11:734–741PubMedCrossRefGoogle Scholar
  35. 35.
    Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt W, Mehta P, Craft S (2008) Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 70:440–448PubMedCrossRefGoogle Scholar
  36. 36.
    Ritchie K, Artero S, Touchon J (2001) Classification criteria for mild cognitive impairment: a population-based validation study. Neurology 56:37–42PubMedGoogle Scholar
  37. 37.
    Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT (1998) A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease: Donepezil Study Group. Neurology 50:136–145PubMedGoogle Scholar
  38. 38.
    Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stähelin HB, Hartman R, Gharabawi M (1999) Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 318:633–638PubMedGoogle Scholar
  39. 39.
    Sabbagh MN, Farlow MR, Relkin N, Beach TG (2006) Do cholinergic therapies have disease-modifying effects in Alzheimer’s disease? Alzheimers Dement 2:118–125CrossRefGoogle Scholar
  40. 40.
    Salloway S, Ferris S, Kluger A, Goldman R, Griesing T, Kumar D, Richardson S (2004) Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology 63:651–657PubMedGoogle Scholar
  41. 41.
    Saykin AJ, Wishart HA, Rabin LA, Flashman LA, McHugh TL, Mamourian AC, Santulli RB (2004) Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Brain 127:1574–1583PubMedCrossRefGoogle Scholar
  42. 42.
    Small GW, Kaufer D, Mendiondo MS, Quarg P, Spiegel R (2005) Cognitive performance in Alzheimer’s disease patients receiving rivastigmine for up to 5 years. Int J Clin Pract 59:473–477PubMedCrossRefGoogle Scholar
  43. 43.
    Vellas B, Andrieu S, Sampaio C, Coley N, Wilcock G, for the European Task Force Group (2008) Endpoints for trials in Alzheimer’s disease: a European task force consensus. Lancet Neurol 7:436–450PubMedCrossRefGoogle Scholar
  44. 44.
    Visser PJ, Sheltens P, Verhey FRJ (2005) Do MCI criteria in drug trials accurately identify subjects with pre-dementia Alzheimer’s disease? J Neurol Neurosurg Psychiatry 76: 1348–1354PubMedCrossRefGoogle Scholar
  45. 45.
    Whitwell JL, Shiung MM, Przybelski SA, Weigand SD, Knopman DS, Boeve BF, Petersen RC, Jack CR Jr (2008) MRI patterns of atrophy associated with progression to AD in amnestic mild cognitive impairment. Neurology 70: 512–520PubMedCrossRefGoogle Scholar
  46. 46.
    Wilcock GK, Lilienfeld S, Gaens E (2000) Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ 321:1445–1449PubMedCrossRefGoogle Scholar
  47. 47.
    Wilkinson DG, Passmore AP, Bullock R, Hopker SW, Smith R, Potocnik FC, Maud CM, Engelbrecht I, Hock C, Ieni JR, Bahra RS (2002) A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer’s disease. Int J Clin Pract 56:441–446PubMedGoogle Scholar
  48. 48.
    Wimo A, Winblad B, Jönsson L (2007) An estimate of the total worldwide societal costs of dementia in 2005. Alzheimers Dement 3:81–91CrossRefGoogle Scholar
  49. 49.
    Winblad B, Gauthier S, Scinto L, Feldman H, Wilcock GK, Truyen L, Mayorga AJ, Wang D, Brashear HR, Nye JS (2008) Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 70:2024–2035PubMedCrossRefGoogle Scholar
  50. 50.
    Wolf BA, Wertkin AM, Jolly YC, Yasuda RP, Wolfe BB, Konrad RJ, Manning D, Ravi S, Williamson JR, Lee VM (1995) Muscarinic regulation of Alzheimer’s disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells. J Biol Chem 270:4916–4922PubMedCrossRefGoogle Scholar

Copyright information

© Steinkopff Verlag Darmstadt 2009

Authors and Affiliations

  • Breno Satler Diniz
    • 1
  • Jony Arrais PintoJr
    • 1
  • Maria Luiza Cavichioli Gonzaga
    • 1
  • Fabiana Meira Guimarães
    • 1
  • Wagner Farid Gattaz
    • 1
  • Orestes Vicente Forlenza
    • 1
  1. 1.Laboratory of Neuroscience (LIM 27), Institute and Department of Psychiatry, Faculty of MedicineUniversity of Sao PauloSao PauloBrazil

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