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Cited by 182Dementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative DiseasesAlzheimer's disease research and treatments

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Long-term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality

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Xu, Hong, Garcia-Ptacek, Sara, Jönsson, Linus, Wimo, Anders, Nordström, Peter, Eriksdotter, Maria·2021·Neurology
DOI 10.1212/wnl.0000000000011832PMC PMC8166426
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Abstract

OBJECTIVE: To investigate whether cholinesterase inhibitors (ChEIs) are associated with slower cognitive decline in Alzheimer dementia and decreased risk of severe dementia or death. METHODS: Patients with Alzheimer dementia from the Swedish Dementia Registry starting on ChEIs within 3 months of the dementia diagnosis were included and compared to nontreated patients with Alzheimer dementia. In a propensity score-matched cohort, the association between ChEI use and cognitive trajectories assessed by Mini-Mental State Examination (MMSE) scores was examined with a mixed model, and severe dementia (MMSE score <10) or death as an outcome was assessed with Cox proportional hazards models. RESULTS: The matched cohort included 11,652 ChEI users and 5,826 nonusers. During an average of 5 years of follow-up, 255 cases developed severe dementia, and 6,055 (35%) died. ChEI use was associated with higher MMSE score at each visit (0.13 MMSE points per year; 95% confidence interval [CI] 0.06-0.20). ChEI users had a 27% lower risk of death (0.73, 95% CI 0.69-0.77) compared with nonusers. Galantamine was associated with lower risk of death (0.71, 95% CI 0.65-0.76) and lower risk of severe dementia (0.69, 95% CI 0.47-1.00) and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points per year, 95% CI 0.07-0.28). CONCLUSIONS: ChEIs are associated with cognitive benefits that are modest but persist over time and with reduced mortality risk, which could be explained partly by their cognitive effects. Galantamine was the only ChEI demonstrating a significant reduction in the risk of developing severe dementia. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with Alzheimer dementia ChEIs decrease long-term cognitive decline and risk of death and that galantamine decreases the risk of severe dementia.

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Crossref · 10.1212/wnl.0000000000011832

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Figure 1 Flowchart of Included Patients ChEI = cholinesterase inhibitors; MMSE = Mini-Mental State Examination.
Figure 1 Flowchart of Included Patients ChEI = cholinesterase inhibitors; MMSE = Mini-Mental State Examination.CC BY · PubMed Central
Figure 2 Dose Response of ChEIs Using Cubic Splines With (A) MMSE Change and (B) All-Cause Death Risk Compared With Nonuse Dose-response effect of increasing average cumulative daily dose of cholinesterase inhibitor (ChEI) compared to nonuse of ChEI: average (solid) and 95% confidence interval (dash lines). Horizontal axis represents the number of standard defined daily doses (DDDs) that patients took per day. For clarity, the DDD for each medication is shown with a vertical dotted line. For example, a patient taking galantamine 8 mg/d would be taking half the DDD of galantamine, which would be represented at the 0.5 point of the horizontal axis. In panel A, y-axis represents Mini-Mental State Examination (MMSE) score change. In panel B, y-axis represents adjusted hazard ratio for death. Model included ChEI treatment, visit time (class effect), interaction of ChEI treatment by visit, and baseline MMSE score. Reference was set at DDD 0. Cohort was matched for dementia diagnosis, age, sex, MMSE baseline score, comorbidity (hypertension, diabetes, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, renal disease, cancer, and atrial fibrillation), and medications (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blocking agents, calcium channel blockers, lipid-modifying agents, antipsychotics, and antidepressants).
Figure 2 Dose Response of ChEIs Using Cubic Splines With (A) MMSE Change and (B) All-Cause Death Risk Compared With Nonuse Dose-response effect of increasing average cumulative daily dose of cholinesterase inhibitor (ChEI) compared to nonuse of ChEI: average (solid) and 95% confidence interval (dash lines). Horizontal axis represents the number of standard defined daily doses (DDDs) that patients took per day. For clarity, the DDD for each medication is shown with a vertical dotted line. For example, a patient taking galantamine 8 mg/d would be taking half the DDD of galantamine, which would be represented at the 0.5 point of the horizontal axis. In panel A, y-axis represents Mini-Mental State Examination (MMSE) score change. In panel B, y-axis represents adjusted hazard ratio for death. Model included ChEI treatment, visit time (class effect), interaction of ChEI treatment by visit, and baseline MMSE score. Reference was set at DDD 0. Cohort was matched for dementia diagnosis, age, sex, MMSE baseline score, comorbidity (hypertension, diabetes, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, renal disease, cancer, and atrial fibrillation), and medications (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blocking agents, calcium channel blockers, lipid-modifying agents, antipsychotics, and antidepressants).CC BY · PubMed Central

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Cites

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Metadata

Authors
Xu, H., Garcia-Ptacek, S., Jönsson, L., Wimo, A., Nordström, P., & Eriksdotter, M.
Affiliations
  • Karolinska University Hospital (SE)
  • From the Division of Clinical Geriatrics (H.X., S.G.-P., M.E.), Division of Neurogeriatrics (L.J., A.W.), Department of Neurobiology, Care Sciences and Society, and Department of Medical Epidemiology and Biostatistics (H.X.), Karolinska Institutet; Department of Internal Medicine (S.G.-P.), Neurology Section, Södersjukhuset, Stockholm, Sweden; H. Lundbeck A/S (L.J.), Copenhagen, Denmark; Department of Community Medicine and Rehabilitation (P.N.), Geriatric Medicine, Umeå University; and Theme Aging ...
Corresponding author
Xu, Hong
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-04-27
Volume
96
Issue
17
Pages
e2220-e2230
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000011832
PMC
PMC8166426
OpenAlex
W3138811377
Cited by
182
References
9
Citations by year
2026: 23 · 2025: 32 · 2024: 26 · 2023: 35 · 2022: 49 · 2021: 16
FWCI
22.60
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
Funders
  • Svenska Sällskapet för Medicinsk Forskning
  • Karolinska Institutet
  • Stockholms Läns Landsting
  • Umeå Universitet
  • Forskningsrådet om Hälsa, Arbetsliv och Välfärd
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
cholinesterase inhibitors, Alzheimer's disease, cognitive decline, mortality, galantamine, advanced dementia, Mini-Mental State Examination, long-term treatment outcomes
MeSH terms
Mental Status and Dementia Tests, Aged, Aged, 80 and over, Alzheimer Disease, Cholinesterase Inhibitors, Female, Humans, Male, Time, Cohort Studies, Proportional Hazards Models, Cognitive Dysfunction

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