Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer’s Disease: Systematic Review and Network Metaanalysis
Open accessAbstract
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.
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All three acetylcholinesterase inhibitor drugs delay neurodegeneration and stabilise cognition when used in patients with mild to severe Alzheimer's disease symptoms, as shown in clinical trials.
“All three drugs delay neurodegeneration and stabilise cognition when used in patients with mild to severe AD symptoms, as shown in clinical trials.”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [36]
Between 5 and 20% of patients treated with acetylcholinesterase inhibitors show adverse effects mainly associated with the digestive, cardiac, and pulmonary systems.
“reports indicate that between 5 and 20% of patients show adverse effects mainly associated with the digestive, cardiac and pulmonary systems”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [36]
Memantine is normally well-tolerated without the gastrointestinal adverse effects presented by acetylcholinesterase inhibitors, but some patients manifest dizziness, constipation, headache, cough, and drowsiness.
“It is normally well-tolerated without the adverse effects presented by the AChEI at the gastrointestinal level, which are the most severe; however, some patients have manifested negative effects such as dizziness, constipation, headache, cough, and drowsiness [33,35,36].”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [36]
Anti-AD therapies, whether as cholinesterase inhibitor or memantine monotherapy or as add-on dual combination therapy, have demonstrated short-term and long-term benefits to reduce decline in cognition and function.
“A pharmacologic foundation of anti-AD therapies, whether with a ChEI or memantine monotherapy, or, ultimately, combined together as add-on dual combination therapy, most often as memantine added on to stable background ChEI treatment, have demonstrated benefits in the short-term and long-term to reduce decline in cognition and function”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [64]
A recent systematic review and meta-analysis by Tricco and colleagues included 110 studies and 23,432 subjects and supports efficacy, effectiveness, and safety of anti-AD therapies.
“A recent systematic review and meta-analysis by Tricco and colleagues 64 included 110 studies and 23,432 subjects supports efficacy, effectiveness, and safety.”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [64]
With slow titration in appropriate individuals, cholinesterase inhibitors are generally tolerated well and have an acceptable adverse effect profile.
“With slow titration in appropriate individuals, ChEIs are generally tolerated well and have an acceptable adverse effect profile.64”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [64]
Anti-AD therapies retard the emergence and impact of neuropsychiatric symptoms.
“retard the emergence and impact of neuropsychiatric symptoms”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [64]
Anti-AD therapies delay nursing home placement without prolongation of time to death.
“and to delay nursing home placement without prolongation of time to death.64,65”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [64]
Addition of memantine to stable dosages of a cholinesterase inhibitor does not correspond to significant overall increases in adverse events.
“Addition of memantine to stable dosages of a ChEI does not correspond to significant overall increases in adverse events.63,64”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [64]
Memantine monotherapy has demonstrated short- and long-term benefits for patients with moderate to severe Alzheimer disease as assessed by scales evaluating activities of daily living, cognition, and behavioral and psychological symptoms of dementia.
“Memantine monotherapy has demonstrated short- and long-term benefits for patients with moderate to severe AD as assessed by different scales evaluating activities of daily living, cognition, and behavioral and psychological symptoms of dementia (BPSD).19”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [19]
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- Authors
- Tricco, A. C., Ashoor, H. M., Soobiah, C., Rios, P., Veroniki, A. A., Hamid, J. S., Ivory, J. D., Khan, P. A., Yazdi, F., Ghassemi, M., Blondal, E., Ho, J. M., Ng, C. H., Hemmelgarn, B., Majumdar, S. R., Perrier, L., & Straus, S. E.
- Affiliations
- St. Michael's Hospital (CA)
- University of Calgary (CA)
- University of Alberta (CA)
- University of Toronto (CA)
- Corresponding author
- Straus, Sharon E.
- ORCID
- Venue
- Journal of the American Geriatrics Society
- Publisher
- Wiley
- Published
- 2017-09-29
- Volume
- 66
- Issue
- 1
- Pages
- 170-178
- ISSN
- 0002-8614 (ISSN-L)
- 1532-5415
- OpenAlex
- W2759099753
- Cited by
- 137
- References
- 41
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 16 · 2023: 12 · 2022: 21 · 2021: 12 · 2020: 18 · 2019: 21 · 2018: 10 · 2017: 1
- FWCI
- 2.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of the American Geriatrics Society (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- University of Alberta
- University of Toronto
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, nootropic drugs, cholinesterase inhibitors, donepezil, rivastigmine, galantamine, memantine, cognitive function, behavioral symptoms, drug safety, comparative effectiveness, Mini-Mental State Examination
- MeSH terms
- Alzheimer Disease, Cholinesterase Inhibitors, Cognition, Cost-Benefit Analysis, Humans, Dopamine Agents, Patient Safety
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