EFNS ‐ ENS / EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's disease
Open accessAbstract
BACKGROUND AND PURPOSE: Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL). METHODS: A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95% CI -0.37; -0.17) and behaviour (SMD -0.19; 95% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak. CONCLUSIONS: We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.
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Combined use of memantine with ChEIs shows slight cognitive and functional benefits in moderate to severe Alzheimer's disease.
“Combined use with ChEIs, memantine shows slight cognitive and functional benefits in moderate to severe AD.29,30”
From A 2025 update on treatment strategies for the Alzheimer’s disease spectrum (2025) · cites this paper as [30]
The Meta-analyses section reports a small, significant cognitive benefit from combined treatment in moderate to severe AD. It found no statistically significant overall benefit for activities of daily living, so the claimed functional benefit is not established by this paper. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredCholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine are the only FDA-approved treatments for AD dementia.
“Cholinesterase inhibitors (ChEIs) (donepezil, galantamine, rivastigmine) and the N-methyl-D-aspartate (NMDA)-antagonist, memantine, are the only FDA-approved treatments for AD dementia and are recommended broadly in consensus guidelines and practice parameters.1,52,61,62”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [61]
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- Authors
- Schmidt, R., Hofer, E., Bouwman, F. H., Buerger, K., Cordonnier, C., Fladby, T., Galimberti, D., Georges, J., Heneka, M. T., Hort, J., Laczó, J., Molinuevo, J. L., O'Brien, J. T., Religa, D., Scheltens, P., Schott, J. M., & Sorbi, S.
- Affiliations
- Medical University of Graz (AT)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Institute for Stroke and Dementia Research (ISD) Klinikum der Universität München Campus Großhadern Munich Germany
- Université de Lille (FR)
- Akershus University Hospital (NO)
- University of Milan (IT)
- Alzheimer Europe (LU)
- German Center for Neurodegenerative Diseases (DE)
- Charles University (CZ)
- Hospital Clínic de Barcelona (ES)
- University of Cambridge (GB)
- Karolinska University Hospital (SE)
- National Hospital for Neurology and Neurosurgery (GB)
- University of Florence (IT)
- Corresponding author
- Schmidt, R.
- ORCID
- Venue
- European Journal of Neurology
- Publisher
- Wiley
- Published
- 2015-03-25
- Volume
- 22
- Issue
- 6
- Pages
- 889-898
- ISSN
- 1351-5101 (ISSN-L)
- 1468-1331
- OpenAlex
- W2092841864
- Cited by
- 140
- References
- 27
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 10 · 2023: 10 · 2022: 14 · 2021: 19 · 2020: 16 · 2019: 18 · 2018: 10 · 2017: 7 · 2016: 14 · 2015: 5 · 2013: 1
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Journal of Neurology (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- DZNE Pub (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Exelon Corporation
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, cholinesterase inhibitors, memantine, combination therapy, moderate to severe dementia, cognitive function, behavioural symptoms, activities of daily living, treatment guidelines
- MeSH terms
- Alzheimer Disease, Cholinesterase Inhibitors, Drug Therapy, Combination, Humans, Memantine, Practice Guidelines as Topic, Excitatory Amino Acid Antagonists
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