Drugs & Aging

, Volume 24, Issue 11, pp 881–890

Is Long-Term Treatment of Alzheimer’s Disease with Cholinesterase Inhibitor Therapy Justified?

Current Opinion


The cholinesterase inhibitors (ChEIs) donepezil, rivastigmine and galantamine are the current mainstays in the drug treatment of Alzheimer’s disease (AD). There is convincing evidence that these agents provide at least modest cognitive, behavioural and functional benefit for 6–12 months at all stages of the disease. Longer term benefits cannot be directly examined by placebo-controlled trials. Nevertheless, the results of virtually all open-label extensions of the pivotal trials, studies of patients with AD at different levels of severity and clinical trials using other designs favour treatment over no treatment for periods of up to 5 years. There are plausible biological reasons why ChEIs might be expected to work over a prolonged period of time although, to date, studies using various markers to chart the effects of medication on long-term disease progression have yielded mixed results. The most contentious issue regarding long-term treatment is economic, but the majority of available economic analyses suggest net savings over the long term if patients with AD receive persistent treatment with ChEIs.


  1. 1.
    Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’: a practical method for grading the cognitive state of subjects for the clinician. J Psychiatr Res 1975; 12(3): 189–98PubMedCrossRefGoogle Scholar
  2. 2.
    Farlow M, Gracon SJ, Hershey LA, et al. A controlled trial of tacrine in Alzheimer’s disease. JAMA 1992; 268: 2523–9PubMedCrossRefGoogle Scholar
  3. 3.
    Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease: Donepezil Study Group. Neurology 1998; 50: 136–45PubMedCrossRefGoogle Scholar
  4. 4.
    Burns A, Rossor M, Hecker J, et al. The effects of donepezil in Alzheimer’s disease: results from a multinational trial. Dement Geriatr Cogn Disord 1999; 10: 237–44PubMedCrossRefGoogle Scholar
  5. 5.
    Corey-Bloom J, Anand R, Veach J, et al. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease. Int J Geriatr Psychopharmacol 1998; 1: 55–65Google Scholar
  6. 6.
    Rosier M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 1999; 318: 633–8Google Scholar
  7. 7.
    Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6 month extension: the Galantamine USA-1 Study Group. Neurology 2000; 54: 2261–8PubMedCrossRefGoogle Scholar
  8. 8.
    Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD: the Galantamine USA-10 Study Group. Neurology 2000; 54: 2269–76PubMedCrossRefGoogle Scholar
  9. 9.
    Wilcock GK, Lilienfeld S, Gaens E, et al. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomized controlled trial. Galantamine International-1 Study Group. BMJ 2000; 321: 1445–9PubMedCrossRefGoogle Scholar
  10. 10.
    Alexopoulos GS, Jeste DV, Chung H, et al. The expert consensus guideline series: treatment of dementia and its behavioral disturbances. Introduction: methods, commentary, and summary. Postgrad Med 2005 Jan; Spec No: 6-22Google Scholar
  11. 11.
    Fillit HM, Doody RS, Binaso K, et al. Recommendations for best practices in the treatment of Alzheimer’s disease in managed care. Am J Geriatr Pharmacother 2006; 4Suppl. 1: S9–24PubMedCrossRefGoogle Scholar
  12. 12.
    Burns A, O’Brien J. Clinical practice with anti-dementia drugs: a consensus statement from the British Association for Psychopharmacology. J Psychopharmacol 2006 Nov; 20(6): 732–55PubMedCrossRefGoogle Scholar
  13. 13.
    Caltagirone C, Bianchetti A, Di Luca M, et al. Guidelines for the treatment of Alzheimer’s disease from the Italian Association of Psychogeriatrics. Drugs Aging 2005; 22Suppl. 1: 1–26PubMedGoogle Scholar
  14. 14.
    Jost BC, Grossberg GT. The natural history of Alzheimer’s disease: a brain bank study. J Am Geriatr Soc 1995 Nov; 43(11): 1248–55PubMedGoogle Scholar
  15. 15.
    Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001 Aug 14; 57(3): 489–95PubMedCrossRefGoogle Scholar
  16. 16.
    Mohs RC, Doody RS, Morris JC, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001; 57(3): 481–8PubMedCrossRefGoogle Scholar
  17. 17.
    Almkvist O, Darreh-Shori T, Stefanova E, et al. Preserved cognitive function after 12 months of treatment with rivastigmine in mild Alzheimer’s disease in comparison with untreated AD and MCI patients. Eur J Neurol 2004 Apr; 11(4): 253–61PubMedCrossRefGoogle Scholar
  18. 18.
    Karaman Y, Erdogan F, Koseoglu E, et al. A 12-month study of the efficacy of rivastigmine in patients with advanced moderate Alzheimer’s disease. Dement Geriatr Cogn Disord 2005; 19(1): 51–6PubMedCrossRefGoogle Scholar
  19. 19.
    Auer S, Reisberg B. The GDS/FAST staging systems. Int Psychogeriatr 1997; 9Suppl. 1: 167–71PubMedCrossRefGoogle Scholar
  20. 20.
    Seltzer B, Zolnouni P, Nunez M, et al. Efficacy of donepezil in early-stage Alzheimer disease. Arch Neurol 2004 Dec; 61: 1852–6PubMedCrossRefGoogle Scholar
  21. 21.
    Feldman H, Gauthier S, Hecker J, et al. A 24 week-, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 2001; 57(4): 613–20PubMedCrossRefGoogle Scholar
  22. 22.
    Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006; 367(9516): 1057–65PubMedCrossRefGoogle Scholar
  23. 23.
    Tariot PN, Cummings JL, Katz IR, et al. A randomized, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc 2001; 49(12): 1590–9PubMedCrossRefGoogle Scholar
  24. 24.
    Potkin SG, Anand R, Hartman R, et al. Impact of Alzheimer’s disease and rivastigmine treatment on activities of daily living over the course of mild to moderately severe disease. Prog Neuropsychopharmacol Biol Psychiatry 2002 May; 26: 713–20CrossRefGoogle Scholar
  25. 25.
    Kurz A, Farlow M, Quarg P, et al. Disease stage in Alzheimer disease and treatment effects of rivastigmine. Alzheimer Dis Assoc Disord 2004 Jul-Sept; 18: 123–8PubMedCrossRefGoogle Scholar
  26. 26.
    Doody RS, Geldmacher DS, Gordon B, et al. Open-label, mul-ticenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol 2001 Mar; 58: 427–33PubMedCrossRefGoogle Scholar
  27. 27.
    Winblad B, Engedal K, Soininen H, et al. Long-term efficacy of donepezil in patients with mild to moderate Alzheimer’s disease: results from a 1-year, placebo-controlled study and two year follow up study. Int Psychogeriatr 2003; 15Suppl. 2: 293–4Google Scholar
  28. 28.
    Winblad B, Wimo A, Engedal K, et al. 3-year study of donepezil therapy in Alzheimer’s disease: effects of early and continuous therapy. Dement Geriatr Cogn Disord 2006; 21(5–6): 353–63PubMedCrossRefGoogle Scholar
  29. 29.
    Burns A, Gauthier S, Perdomo C. Efficacy and safety of donepezil over 3 years: an open-label, multicentre study in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 2007 Aug; 22(8): 806–12PubMedCrossRefGoogle Scholar
  30. 30.
    Raskind MA, Peskind ER, Truyen L, et al. The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol 2004 Feb; 61: 252–6PubMedCrossRefGoogle Scholar
  31. 31.
    Pirttila T, Wilcock G, Truyen L, et al. Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease: multicenter trial. Eur J Neurol 2004 Nov; 11: 734–41PubMedCrossRefGoogle Scholar
  32. 32.
    Farlow M, Anand R, Messina Jr J, et al. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol 2000; 44: 236–41PubMedCrossRefGoogle Scholar
  33. 33.
    Farlow MR, Lilly ML, ENA713 B352 Study Group. Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer’s disease for up to 5 years. BMC Geriatr 2005 Jan 19; 5: 3PubMedCrossRefGoogle Scholar
  34. 34.
    Rogers SL, Doody RS, Pratt RD, et al. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open-label study. Eur Neuropsychopharmacol 2000; 10: 195–203PubMedCrossRefGoogle Scholar
  35. 35.
    Kramer-Ginsberg E, Mohs RC, Aryan M, et al. Clinical predictors of the course of Alzheimer’s disease patients in a longitudinal study: a preliminary report. Psychopharmacol Bull 1988; 24: 458–62PubMedGoogle Scholar
  36. 36.
    Doody RS, Dunn JK, Clark CM, et al. Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer’s disease. Dement Geriatr Cogn Disord 2001; 12: 295–300PubMedCrossRefGoogle Scholar
  37. 37.
    Lopez OL, Becker JT, Wisniewski S, et al. Cholinesterase inhibitor treatment alters the natural course of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002; 72: 310–4PubMedCrossRefGoogle Scholar
  38. 38.
    Geldmacher DS, Provenzano G, McRae T, et al. Donepezil is associated with delayed nursing home placement in patients with Alzheimer’s disease. J Am Geriatr Soc 2003; 51: 937–44PubMedCrossRefGoogle Scholar
  39. 39.
    Bullock R, Dengiz A. Cognitive performance in patients with Alzheimer’s disease receiving cholinesterase inhibitors for up to 5 years. Int J Clin Pract 2005 Jul; 59(7): 817–22PubMedCrossRefGoogle Scholar
  40. 40.
    Winblad B, Jelic V. Long-term treatment of Alzheimer disease: efficacy and safety of acetylcholinesterase inhibitors. Alzheimer Dis Assoc Disord 2004 Apr-Jun; 18Suppl. 1: S2–8PubMedCrossRefGoogle Scholar
  41. 41.
    Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984; 141(11): 1356–64PubMedGoogle Scholar
  42. 42.
    McLendon BM, Doraiswamy PM. Defining meaningful change in Alzheimer’s disease trials: the donepezil experience. J Geriatr Psychiatry Neurol 1999 Spring; 12: 39–48PubMedCrossRefGoogle Scholar
  43. 43.
    Johannsen P, Salmon E, Hampel H, et al. Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer’s disease. CNS Drugs 2006; 20(4): 311–25PubMedCrossRefGoogle Scholar
  44. 44.
    Klinger T, Ibach B, Schoenknecht P, et al. Effect of donepezil in patients with Alzheimer’s disease previously untreated or treated with memantine or nootropic agents in Germany: an observational study. Curr Med Res Opin 2005 May; 21(5): 723–32PubMedCrossRefGoogle Scholar
  45. 45.
    Bartorelli L, Giraldi C, Saccardo M, et al. Effects of switching from an AChE inhibitor to a dual AChE-BuChE inhibitor in patients with Alzheimer’s disease. Curr Med Res Opin 2005 Nov; 21(11): 1809–18PubMedCrossRefGoogle Scholar
  46. 46.
    Auriacombe S, Pere JJ, Loria-Kanza Y, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease who failed to benefit from treatment with donepezil. Curr Med Res Opin 2002; 18(3): 129–38PubMedCrossRefGoogle Scholar
  47. 47.
    Gauthier S, Emre M, Farlow MR, et al. Strategies for continued successful treatment of Alzheimer’s disease: switching cholinesterase inhibitors. Curr Med Res Opin 2003; 19(8): 707–14PubMedCrossRefGoogle Scholar
  48. 48.
    Drachman DA, Leavitt J. Human memory and the cholinergic system: a relationship to aging? Arch Neurol 1974; 30: 113–21PubMedCrossRefGoogle Scholar
  49. 49.
    Bartus RT, Dean 3rd RL, Beer B, et al. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217: 408–17PubMedCrossRefGoogle Scholar
  50. 50.
    Whitehouse PJ, Price DL, Struble RG, et al. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 1982; 215(4537): 1237–9PubMedCrossRefGoogle Scholar
  51. 51.
    Davies KL, Mohs RC, Marin D, et al. Cholinergic markers in elderly patients with early signs of Alzheimer’s disease. JAMA 1999; 21: 1401–6CrossRefGoogle Scholar
  52. 52.
    Giacobini E. Selective inhibitors of butyrylcholinesterase: a valid alternative for therapy of Alzheimer’s disease? Drugs Aging 2001; 18(12): 891–8PubMedCrossRefGoogle Scholar
  53. 53.
    Amici S, Lanari A, Romani R, et al. Cerebrospinal fluid acetylcholinesterase activity after long-term treatment with donepezil and rivastigmine. Mech Ageing Dev 2001 Nov; 122(16): 2057–62PubMedCrossRefGoogle Scholar
  54. 54.
    Darreh-Shori T, Almkvist O, Guan ZZ, et al. Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months. Neurology 2002 Aug 27; 59(4): 563–72PubMedCrossRefGoogle Scholar
  55. 55.
    Darreh-Shori T, Hellstrom-Lindahl E, Flores-Flores C, et al. Long-lasting acetylcholinesterase splice variations in acetyl-cholinesterase-treated Alzheimer’s disease patients. J Neurochem 2004 Mar; 88(5): 1102–13PubMedCrossRefGoogle Scholar
  56. 56.
    Cummings JL. Challenges to demonstrating disease-modifying effects in Alzheimer’s disease clinical trials. Alzheimers Dement 2006; 2(4): 263–71PubMedCrossRefGoogle Scholar
  57. 57.
    Sabbagh MS, Farlow MR, Relkin N, et al. Do cholinergic therapies have a disease-modifying effect in Alzheimer’s disease? Alzheimers Dement 2006; 2: 118–25PubMedCrossRefGoogle Scholar
  58. 58.
    Sampaio C. Alzheimer’s disease: disease modifying trials. Where are we? Where do we need to go? A reflective paper. J Nutr Health Aging 2006; 10: 113–5PubMedGoogle Scholar
  59. 59.
    Lane RM, Kivipelto M, Greig NH. Acetylcholinesterase and its inhibition in Alzheimer disease. Clin Neuropharmacol 2004 May-Jun; 27(3): 141–9PubMedCrossRefGoogle Scholar
  60. 60.
    Nordberg A. Emerging biology of the cholinergic system across the spectrum of Alzheimer’s disease. Int Psychogeriatr 2006; 18Suppl. 1: S3–16CrossRefGoogle Scholar
  61. 61.
    Farlow MR. Do cholinesterase inhibitors slow progression of Alzheimer’s disease? Int J Clin Pract Suppl 2002 Jun; 127: 37–44PubMedGoogle Scholar
  62. 62.
    Seltzer B. Cholinesterase inhibitors in the clinical management of Alzheimer’s disease: importance of early and persistent treatment. J Int Med Res 2006; 34: 339–47PubMedGoogle Scholar
  63. 63.
    Akaike A. Preclinical evidence of neuroprotection by cholinesterase inhibitors. Alzheimer Dis Assoc Disord 2006 Apr-Jun; 20 (2 Suppl. 1): S8–11PubMedCrossRefGoogle Scholar
  64. 64.
    Nordberg A. Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer’s disease. Alzheimer Dis Assoc Disord 2006 Apr-Jun; 20Suppl. 1: S12–8PubMedCrossRefGoogle Scholar
  65. 65.
    DeKosky ST, Ikonomovic MD, Styren SD, et al. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002; 51: 145–55PubMedCrossRefGoogle Scholar
  66. 66.
    Mufson EJ, Ma SY, Dillis J, et al. Loss of basal forebrain P75(NTR) immunoreactivity in subjects with mild cognitive impairment and Alzheimer’s disease. J Comp Neurol 2002; 443(2): 136–53PubMedCrossRefGoogle Scholar
  67. 67.
    Riepe MW. Cholinergic treatment: what are the early neuropathological targets? Eur J Neurol 2005; 12Suppl. 3: 3–9PubMedCrossRefGoogle Scholar
  68. 68.
    Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. New Engl J Med 2005; 352(23): 2379–88PubMedCrossRefGoogle Scholar
  69. 69.
    Greig NH, Lahiri DK, Sambamurti K. Butyrylcholinesterase: an important target in Alzheimer’s disease therapy. Int Psychogeriatr 2002; 14Suppl. 1: 77–91PubMedCrossRefGoogle Scholar
  70. 70.
    Eskander MF, Nagykery NG, Leung EY, et al. Rivastigmine is a potent inhibitor of acetyl- and butyrylcholinesterase in Alzheimer’s plaques and tangles. Brain Res 2005 Oct 26; 1060(1–2): 144–52PubMedCrossRefGoogle Scholar
  71. 71.
    Albuquerque EX, Santos MD, Alkondon M, et al. Modulation of nicotinic receptor activity in the central nervous system: a novel approach to the treatment of Alzheimer disease. Alzheimer Dis Assoc Disord 2001 Aug; 15Suppl. 1: S19–25PubMedCrossRefGoogle Scholar
  72. 72.
    Lilienfeld S. Galantamine: a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer’s disease. CNS Drug Rev 2002 Summer; 8(2): 159–76PubMedCrossRefGoogle Scholar
  73. 73.
    Geerts H. Indicators of neuroprotection with galantamine. Brain Res Bull 2005 Jan 30; 64(6): 519–24PubMedCrossRefGoogle Scholar
  74. 74.
    Kimura M, Akasofu S, Ogura H, et al. Protective effect of donepezil against Abeta(1–40) neurotoxicity in rat septal neurons. Brain Res 2005; 1047(1): 72–84PubMedCrossRefGoogle Scholar
  75. 75.
    Reid RT, Sabbagh MR. Effects of donepezil treatment on rat nicotinic receptor levels in vivo and in vitro. J Alzheimer’s Res 2003; 5(6): 429–36Google Scholar
  76. 76.
    Takada-Takatori Y, Kume T, Sugimoto S, et al. Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology 2006; 51(3): 474–86PubMedCrossRefGoogle Scholar
  77. 77.
    Krishnan KR, Charles HC, Doraiswamy PM, et al. Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease. Am J Psychiatry 2003; 160: 2003–11PubMedCrossRefGoogle Scholar
  78. 78.
    Tune L, Tiseo PJ, Ieni J, et al. Donepezil HC1 (E2020) maintains functional brain activity in patients with Alzheimer’s disease: results of a 24-week, double-blind, placebo-controlled study. Am J Geriatr Psychiatry 2003; 11(2): 169–77PubMedGoogle Scholar
  79. 79.
    Staff RT, Gemmell HG, Shanks MF, et al. Changes in the rCBF images of patients with Alzheimer’s disease receiving donepezil therapy. Nucl Med Commun 2000; 21: 37–41PubMedCrossRefGoogle Scholar
  80. 80.
    Hashimoto M, Kazui H, Matsumoto K, et al. Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer’s disease? Am J Psychiatry 2005 Apr; 162(4): 676–82PubMedCrossRefGoogle Scholar
  81. 81.
    Jack Jr CR, Petersen RC, O’Brien RC, et al. MR-based hippocampal volumetry in the diagnosis of Alzheimer’s disease. Neurology 1992; 42: 183–8PubMedCrossRefGoogle Scholar
  82. 82.
    Nobili F, Vitalu P, Canfora M, et al. Effects of long-term donepezil therapy on rCBF of Alzheimer’s patients. Clin Neurophysiol 2002 Aug; 113(8): 1241–8PubMedCrossRefGoogle Scholar
  83. 83.
    Shimizu S, Hanyu H, Iwamoto T, et al. SPECT follow-up study of cerebral blood flow changes during donepezil therapy in patients with Alzheimer’s disease. J Neuroimaging 2006 Jan; 16(1): 16–23PubMedCrossRefGoogle Scholar
  84. 84.
    Ushujima Y, Okuyama C, Mori S, et al. Regional cerebral blood flow in Alzheimer’s disease: comparison between short and long-term donepezil therapy. Ann Nucl Med 2006 Jul; 20(6): 425–9CrossRefGoogle Scholar
  85. 85.
    Stefanova E, Wall A, Almkvist O, et al. Longitudinal PET evaluation of cerebral glucose utilization in rivastigmine treated patients with mild Alzheimer’s disease. J Neural Transm 2006 Feb; 113(2): 205–18PubMedCrossRefGoogle Scholar
  86. 86.
    Rodriguez G, Vitali P, De Leo C, et al. Quantitative EEG changes in Alzheimer patients during long-term donepezil therapy. Neuropsychobiology 2002; 46(1): 49–56PubMedCrossRefGoogle Scholar
  87. 87.
    Zarit SH, Reeves KE, Bach-Peterson J. Relatives of the impaired elderly: correlates of feelings of burden. Gerontologist 1980; 20(6): 649–55PubMedCrossRefGoogle Scholar
  88. 88.
    Lingler JH, Martire LM, Schulz R. Caregiver-specific outcomes in antidementia clinical drug trials: a systematic review and meta-analysis. J Am Geriatr Soc 2005 Jun; 53(6): 983–90PubMedCrossRefGoogle Scholar
  89. 89.
    Wimo A, Jonsson L, Winblad B. An estimate of the worldwide prevalence and direct costs of dementia in 2003. Dement Geriatr Cogn Disord 2006; 21(3): 175–81PubMedCrossRefGoogle Scholar
  90. 90.
    Courtney C, Farrell D, Gray R, et al. Long term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomized, double-blind trial. Lancet 2004; 363: 2105–15PubMedCrossRefGoogle Scholar
  91. 91.
    Caro J, Salas M, Ward A, et al. Assessing the health and economic impact of galantamine treatment in patients with Alzheimer’s disease in the health care systems of different countries. Drugs Aging 2004; 21(10): 677–86PubMedCrossRefGoogle Scholar
  92. 92.
    Stewart A, Phillips R, Dempsey G. Pharmacotherapy for people with Alzheimer’s disease: a Markov-cycle evaluation of five years’ therapy using donepezil. Int J Geriatr Psychiatry 1998 Jul; 13(7): 445–53PubMedCrossRefGoogle Scholar
  93. 93.
    Jonsson L, Lindgren P, Wimo A, et al. The cost-effectiveness of donepezil therapy in Swedish patients with Alzheimer’s disease: a Markov model. Clin Ther 1999 Jul; 21(7): 1230–40PubMedCrossRefGoogle Scholar
  94. 94.
    Neumann PJ, Hermann RC, Kuntz KM, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer disease. Neurology 1999 Apr 12; 52(6): 1138–45PubMedCrossRefGoogle Scholar
  95. 95.
    O’Brien BJ, Goeree R, Hux M, et al. Economic evaluation of donepezil for the treatment of Alzheimer’s disease in Canada. J Am Geriatr Soc 1999 May; 47(5): 570–8PubMedGoogle Scholar
  96. 96.
    Caro JJ, Getsios D, Migliaccio-Walle K, et al. Assessment of health economics in Alzheimer’s disease (AHEAD) based on need for full-time care. Neurology 2001 Sep 25; 57(6): 964–71PubMedCrossRefGoogle Scholar
  97. 97.
    Getsios D, Caro JJ, Caro G, et al. Assessment of health economics in Alzheimer’s disease (AHEAD): galantamine treatment in Canada. Neurology 2001 Sep 25; 57(6): 972–8PubMedCrossRefGoogle Scholar
  98. 98.
    Garfield FB, Getsios D, Caro JJ, et al. Assessment of Health Economics in Alzheimer’s Disease (AHEAD): treatment with galantamine in Sweden. Pharmacoeconomics 2002; 20(9): 629–37PubMedCrossRefGoogle Scholar
  99. 99.
    Fagnani F, Lafuma A, Pechevis M, et al. Donepezil for the treatment of mild to moderate Alzheimer’s disease in France: the economic implications. Dement Geriatr Cogn Disord 2004; 17(1–2): 5–13PubMedCrossRefGoogle Scholar
  100. 100.
    Feldman H, Gauthier S, Hecker J, et al. Economic evaluation of donepezil in moderate to severe Alzheimer disease. Neurology 2004 Aug 24; 63(4): 644–50PubMedCrossRefGoogle Scholar
  101. 101.
    Clegg A, Bryant J, Nicholson T, et al. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer’s disease: a rapid and systematic review. Health Technol Assess 2001; 5(1): 1–137Google Scholar
  102. 102.
    Evans JG, Wilcock G, Birks J. Evidence-based pharmacotherapy of Alzheimer’s disease. Int J Neuropsychopharmacol 2004 Sep; 7(3): 351–69PubMedCrossRefGoogle Scholar
  103. 103.
    Green C, Picot J, Loveman E, et al. Modelling the cost effectiveness of cholinesterase inhibitors in the management of mild to moderately severe Alzheimer’s disease. Pharmacoeconomics 2005; 23(12): 1271–82PubMedCrossRefGoogle Scholar
  104. 104.
    Loveman E, Green C, Kirby J, et al. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and me-mantine for Alzheimer’s disease. Health Technol Assess 2006 Jan; 10(1): iii–iv, ix–xi, 1–160PubMedGoogle Scholar
  105. 105.
    Sramek JJ, Anand R, Wardle TS, et al. Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer’s disease. Life Sci 1996; 58(15): 1201–7PubMedCrossRefGoogle Scholar
  106. 106.
    Inglis F. The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. Int J Clin Practice Suppl 2002 Jun; 127: 45–63Google Scholar
  107. 107.
    Jackson S, Ham RJ, Wilkinson D. The safety and tolerability of donepezil in patients with Alzheimer’s disease. Br J Clin Pharmacol 2004 Nov; 58Suppl. 1: 1–8PubMedCrossRefGoogle Scholar
  108. 108.
    Birks J, Iakovidou V, Tsolaki M. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev 2000; (2): CD001191Google Scholar
  109. 109.
    Loy C, Schneider L. Galantamine for Alzheimer’s disease. Cochrane Database Syst Rev 2004 Oct 18; (4): CD001747Google Scholar
  110. 110.
    Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev 2006 Jan 25; (1): CD001190Google Scholar
  111. 111.
    Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006 Jan 25; (1): CD005593Google Scholar
  112. 112.
    Takeda A, Loveman E, Clegg A, et al. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer’s disease. Int J Geriatr Psychiatry 2006 Jan; 21(1): 17–28PubMedCrossRefGoogle Scholar
  113. 113.
    Birks J, Flicker L. Donepezil for mild cognitive impairment. Cochrane Database Syst Rev 2006 Jul 19; (3): CD0006104Google Scholar
  114. 114.
    National Institute for Health and Clinical Excellence (UK). Technology appraisal guidance 111: donepezil, galantamine, rivastigmine (review) and memantine for the treatment of Alzheimer’s disease. London: National Institute for Health and Clinical Excellence, 2006 NovGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.VA Boston Healthcare System, Department of NeurologyHarvard Medical SchoolBostonUSA
  2. 2.VA Boston Healthcare System (181JP)BostonUSA

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