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Table of Contents
Vol. 10, No. 1-4, 2012
Issue release date: April 2012
Section title: Paper
Free Access
Neurodegenerative Dis 2012;10:170–174
(DOI:10.1159/000335156)

Validity, Significance, Strengths, Limitations, and Evidentiary Value of Real-World Clinical Data for Combination Therapy in Alzheimer’s Disease: Comparison of Efficacy and Effectiveness Studies

Atri A.a–c · Rountree S.D.d · Lopez O.L.e · Doody R.S.d
aDepartment of Neurology, Massachusetts General Hospital, Boston, Mass., bGeriatric Research, Education and Clinical Center, ENRM VA Medical Center, Bedford, Mass., cHarvard Medical School, Boston, Mass., dAlzheimer’s Disease and Memory Disorders Center, Department of Neurology, Baylor College of Medicine, Houston, Tex., and eDepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pa., USA
email Corresponding Author

Abstract

Background: Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer’s disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness. Objective: To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs). Methods: Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs. Results: RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization. Conclusions: Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed.

© 2012 S. Karger AG, Basel


  

Key Words

  • Comparative effectiveness
  • Evidence grade
  • Dementia treatment
  • Donepezil
  • Galantamine
  • Rivastigmine
  • Memantine
  • Observational trial

References

  1. Godwin M, Ruhland L, Casson I, MacDonald S, Delva D, Birtwhistle R, Lam M, Seguin R: Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity. BMC Med Res Methodol 2003;3:28.

    External Resources

  2. Rothwell PM: External validity of randomised controlled trials: ‘To whom do the results of this trial apply?’ Lancet 2005;365:82–93.
  3. US Preventive Services Task Force: Guide to Clinical Preventive Services: Report of the US Preventive Services Task Force. Philadelphia, Lippincott Williams & Wilkins, 1989, pp 24.
  4. Oxford Centre for Evidence-Based Medicine. Levels of Evidence. 2009, 2011.
  5. Schwartz D, Lellouch J: Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 1967;20:637–648.
  6. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M: Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 1999;318:633–638.
  7. Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, McDonald S: Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 2006;14:704–715.
  8. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ: Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333–1341.
  9. van Dyck CH, Schmitt FA, Olin JT: A responder analysis of memantine treatment in patients with Alzheimer disease maintained on donepezil. Am J Geriatr Psychiatry 2006;14:428–437.
  10. Bakchine S, Loft H: Memantine treatment in patients with mild to moderate Alzheimer’s disease: results of a randomised, double-blind, placebo-controlled 6-month study. J Alzheimers Dis 2008;13:97–107.
  11. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT: A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 1998;50:136–145.
  12. Wilcock GK, Lilienfeld S, Gaens E: Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ 2000;321:1445–1449.
  13. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317–324.
  14. Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT: Memantine treatment in patients with mild to moderate Alzheimer’s disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res 2008;5:83–89.
  15. Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm AL, Zhang R, Haglund A, Subbiah P: A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489–495.
  16. Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, Pratt RD: A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001;57:481–488.
  17. Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P: Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105–2115.
  18. Jones R, Sheehan B, Phillips P, Juszczak E, Adams J, Baldwin A, Ballard C, Banerjee S, Barber B, Bentham P, Brown R, Burns A, Dening T, Findlay D, Gray R, Griffin M, Holmes C, Hughes A, Jacoby R, Johnson T, Knapp M, Lindesay J, McKeith I, McShane R, Macharouthu A, O’Brien J, Onions C, Passmore P, Raftery J, Ritchie C, Howard R: DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer’s disease – A multicentre RCT. Trials 2009;10:57.

    External Resources

  19. Grossberg G, Irwin P, Satlin A, Mesenbrink P, Spiegel R: Rivastigmine in Alzheimer disease: efficacy over two years. Am J Geriatr Psychiatry 2004;12:420–431.
  20. Lyketsos CG, Reichman WE, Kershaw P, Zhu Y: Long-term outcomes of galantamine treatment in patients with Alzheimer disease. Am J Geriatr Psychiatry 2004;12:473–482.
  21. Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV: The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol 2004;61:252–256.
  22. Doody RS, Geldmacher DS, Gordon B, Perdomo CA, Pratt RD: Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol 2001;58:427–433.
  23. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ: A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol 2006;63:49–54.
  24. Khang P, Weintraub N, Espinoza RT: The use, benefits, and costs of cholinesterase inhibitors for Alzheimer’s dementia in long-term care: are the data relevant and available? J Am Med Dir Assoc 2004;5:249–255.

    External Resources

  25. Birks J: Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006:CD005593.
  26. Jones RW, Schwam E, Wilkinson D, Waldemar G, Feldman HH, Zhang R, Albert K, Schindler R: Rates of cognitive change in Alzheimer disease: observations across a decade of placebo-controlled clinical trials with donepezil. Alzheimer Dis Assoc Disord 2009;23:357–364.
  27. McShane R, Areosa Sastre A, Minakaran N: Memantine for dementia. Cochrane Database Syst Rev 2006:CD003154.
  28. Winblad B, Jones RW, Wirth Y, Stoffler A, Mobius HJ: Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord 2007;24:20–27.
  29. Hansen RA, Gartlehner G, Lohr KN, Kaufer DI: Functional outcomes of drug treatment in Alzheimer’s disease: a systematic review and meta-analysis. Drugs Aging 2007;24:155–167.
  30. Rockwood K, Black SE, Robillard A, Lussier I: Potential treatment effects of donepezil not detected in Alzheimer’s disease clinical trials: a physician survey. Int J Geriatr Psychiatry 2004;19:954–960.
  31. Atri A, Shaughnessy LW, Locascio JJ, Growdon JH: Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord 2008;22:209–221.
  32. Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, Klunk W, Dekosky ST: Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009;80:600–607.
  33. Rountree SD, Chan W, Pavlik VN, Darby EJ, Siddiqui S, Doody RS: Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimers Res Ther 2009;1:7.
  34. Wattmo C, Wallin AK, Londos E, Minthon L: Predictors of long-term cognitive outcome in Alzheimer’s disease. Alzheimers Res Ther 2011;3:23.

    External Resources

  35. Wattmo C, Wallin AK, Londos E, Minthon L: Long-term outcome and prediction models of activities of daily living in Alzheimer disease with cholinesterase inhibitor treatment. Alzheimer Dis Assoc Disord 2011;25:63–72.

  

Author Contacts

Alireza Atri, MD, PhD
MGH Memory Disorders Unit
15 Parkman St.
WACC 715, Boston, MA 02114 (USA)
Tel. +1 617 726 1728, E-Mail atri@nmr.mgh.harvard.edu

  

Article Information

Received: September 29, 2011
Accepted after revision: November 15, 2011
Published online: February 10, 2012
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 0, Number of References : 35

  

Publication Details

Neurodegenerative Diseases

Vol. 10, No. 1-4, Year 2012 (Cover Date: April 2012)

Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer’s disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness. Objective: To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs). Methods: Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs. Results: RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization. Conclusions: Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed.

© 2012 S. Karger AG, Basel


  

Author Contacts

Alireza Atri, MD, PhD
MGH Memory Disorders Unit
15 Parkman St.
WACC 715, Boston, MA 02114 (USA)
Tel. +1 617 726 1728, E-Mail atri@nmr.mgh.harvard.edu

  

Article Information

Received: September 29, 2011
Accepted after revision: November 15, 2011
Published online: February 10, 2012
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 0, Number of References : 35

  

Publication Details

Neurodegenerative Diseases

Vol. 10, No. 1-4, Year 2012 (Cover Date: April 2012)

Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Article / Publication Details

First-Page Preview
Abstract of Paper

Received: 9/29/2011 5:24:57 PM
Accepted: 11/15/2011
Published online: 2/10/2012
Issue release date: April 2012

Number of Print Pages: 5
Number of Figures: 1
Number of Tables: 0

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Godwin M, Ruhland L, Casson I, MacDonald S, Delva D, Birtwhistle R, Lam M, Seguin R: Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity. BMC Med Res Methodol 2003;3:28.

    External Resources

  2. Rothwell PM: External validity of randomised controlled trials: ‘To whom do the results of this trial apply?’ Lancet 2005;365:82–93.
  3. US Preventive Services Task Force: Guide to Clinical Preventive Services: Report of the US Preventive Services Task Force. Philadelphia, Lippincott Williams & Wilkins, 1989, pp 24.
  4. Oxford Centre for Evidence-Based Medicine. Levels of Evidence. 2009, 2011.
  5. Schwartz D, Lellouch J: Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 1967;20:637–648.
  6. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M: Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 1999;318:633–638.
  7. Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, McDonald S: Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 2006;14:704–715.
  8. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ: Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333–1341.
  9. van Dyck CH, Schmitt FA, Olin JT: A responder analysis of memantine treatment in patients with Alzheimer disease maintained on donepezil. Am J Geriatr Psychiatry 2006;14:428–437.
  10. Bakchine S, Loft H: Memantine treatment in patients with mild to moderate Alzheimer’s disease: results of a randomised, double-blind, placebo-controlled 6-month study. J Alzheimers Dis 2008;13:97–107.
  11. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT: A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 1998;50:136–145.
  12. Wilcock GK, Lilienfeld S, Gaens E: Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ 2000;321:1445–1449.
  13. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317–324.
  14. Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT: Memantine treatment in patients with mild to moderate Alzheimer’s disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res 2008;5:83–89.
  15. Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm AL, Zhang R, Haglund A, Subbiah P: A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489–495.
  16. Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, Pratt RD: A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001;57:481–488.
  17. Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P: Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105–2115.
  18. Jones R, Sheehan B, Phillips P, Juszczak E, Adams J, Baldwin A, Ballard C, Banerjee S, Barber B, Bentham P, Brown R, Burns A, Dening T, Findlay D, Gray R, Griffin M, Holmes C, Hughes A, Jacoby R, Johnson T, Knapp M, Lindesay J, McKeith I, McShane R, Macharouthu A, O’Brien J, Onions C, Passmore P, Raftery J, Ritchie C, Howard R: DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer’s disease – A multicentre RCT. Trials 2009;10:57.

    External Resources

  19. Grossberg G, Irwin P, Satlin A, Mesenbrink P, Spiegel R: Rivastigmine in Alzheimer disease: efficacy over two years. Am J Geriatr Psychiatry 2004;12:420–431.
  20. Lyketsos CG, Reichman WE, Kershaw P, Zhu Y: Long-term outcomes of galantamine treatment in patients with Alzheimer disease. Am J Geriatr Psychiatry 2004;12:473–482.
  21. Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV: The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol 2004;61:252–256.
  22. Doody RS, Geldmacher DS, Gordon B, Perdomo CA, Pratt RD: Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol 2001;58:427–433.
  23. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ: A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol 2006;63:49–54.
  24. Khang P, Weintraub N, Espinoza RT: The use, benefits, and costs of cholinesterase inhibitors for Alzheimer’s dementia in long-term care: are the data relevant and available? J Am Med Dir Assoc 2004;5:249–255.

    External Resources

  25. Birks J: Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006:CD005593.
  26. Jones RW, Schwam E, Wilkinson D, Waldemar G, Feldman HH, Zhang R, Albert K, Schindler R: Rates of cognitive change in Alzheimer disease: observations across a decade of placebo-controlled clinical trials with donepezil. Alzheimer Dis Assoc Disord 2009;23:357–364.
  27. McShane R, Areosa Sastre A, Minakaran N: Memantine for dementia. Cochrane Database Syst Rev 2006:CD003154.
  28. Winblad B, Jones RW, Wirth Y, Stoffler A, Mobius HJ: Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord 2007;24:20–27.
  29. Hansen RA, Gartlehner G, Lohr KN, Kaufer DI: Functional outcomes of drug treatment in Alzheimer’s disease: a systematic review and meta-analysis. Drugs Aging 2007;24:155–167.
  30. Rockwood K, Black SE, Robillard A, Lussier I: Potential treatment effects of donepezil not detected in Alzheimer’s disease clinical trials: a physician survey. Int J Geriatr Psychiatry 2004;19:954–960.
  31. Atri A, Shaughnessy LW, Locascio JJ, Growdon JH: Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord 2008;22:209–221.
  32. Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, Klunk W, Dekosky ST: Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009;80:600–607.
  33. Rountree SD, Chan W, Pavlik VN, Darby EJ, Siddiqui S, Doody RS: Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimers Res Ther 2009;1:7.
  34. Wattmo C, Wallin AK, Londos E, Minthon L: Predictors of long-term cognitive outcome in Alzheimer’s disease. Alzheimers Res Ther 2011;3:23.

    External Resources

  35. Wattmo C, Wallin AK, Londos E, Minthon L: Long-term outcome and prediction models of activities of daily living in Alzheimer disease with cholinesterase inhibitor treatment. Alzheimer Dis Assoc Disord 2011;25:63–72.