Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer's Disease: Systematic Review and Network Metaanalysis

J Am Geriatr Soc. 2018 Jan;66(1):170-178. doi: 10.1111/jgs.15069. Epub 2017 Sep 29.


Background/objectives: To examine the comparative effectiveness and safety of cognitive enhancers for Alzheimer's disease (AD).

Design: Systematic review and Bayesian network metaanalysis (NMA).

Setting: MEDLINE, EMBASE, Cochrane Library, CINAHL, Ageline (inception-March 2016).

Participants: Individuals with AD in randomized controlled trials (RCTs), quasi-RCTs, and nonrandomized studies.

Intervention: Any combination of donepezil, rivastigmine, galantamine, or memantine.

Measurements: Two reviewers independently screened titles, abstracts, and full-texts; abstracted data; and appraised risk of bias.

Results: Twenty thousand three hundred forty-three citations were screened, and 142 studies were included (110 RCTs, 21 non-RCTs, 11 cohort studies). NMA found that donepezil (Mini-Mental State Examination: mean difference (MD) = 1.39, 95% credible interval (CrI) = 0.53-2.24), donepezil+memantine (2.59, 95% CrI = 0.12-4.98), and transdermal rivastigmine (2.02, 95% CrI = 0.02-4.08) improved cognition more than placebo. NMA found that donepezil (Alzheimer's Disease Assessment Scale-cognitive: MD = -3.29, 95% CrI = -4.57 to -1.99) and galantamine (MD = -2.13, 95% CrI = -3.91 to -0.27) improved cognition more than placebo. NMA found that donepezil+memantine (MD = -5.23, 95% CrI = -8.72 to -1.56) improved behavior more than placebo. NMA found that donepezil (MD = -0.32, 95% CrI = -0.46 to -0.19), donepezil+memantine (MD = -0.57, 95% CrI = -0.95 to -0.21), oral rivastigmine (MD = -0.38, 95% CrI = -0.56 to -0.17), and galantamine (MD = -3.79, 95% CrI = -6.98 to -0.59) improved global status more than placebo. NMA found that galantamine decreased the odds of mortality (odds ratio = 0.56, 95% CrI = 0.36-0.87). No agent increased risk of serious adverse events, falls, or bradycardia. Some increased risk of headache (oral rivastigmine), diarrhea (oral rivastigmine, donepezil), nausea (oral rivastigmine, donepezil, galantamine), and vomiting (oral rivastigmine, donepezil, galantamine).

Conclusion: An exhaustive review of the literature involving 142 studies demonstrated that cognitive enhancers in general have minimal effects on cognition according to minimal clinically important difference and global ratings. The drugs appear safe, but this must be interpreted cautiously because trial participants may have less comorbidity and fewer adverse effects than those treated with these drugs in clinical practice.

Keywords: Alzheimer's disease; cholinesterase inhibitors; knowledge synthesis; network meta-analysis; systematic review.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Cholinesterase Inhibitors / therapeutic use*
  • Cognition / drug effects*
  • Cost-Benefit Analysis*
  • Dopamine Agents / therapeutic use*
  • Humans
  • Patient Safety


  • Cholinesterase Inhibitors
  • Dopamine Agents