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Multi-domain interventions for the prevention of dementia and cognitive decline
Open accessAbstract
BACKGROUND: Dementia is a worldwide concern. Its global prevalence is increasing. Currently, no effective medical treatment exists to cure or to delay the onset of cognitive decline or dementia. Up to 40% of dementia is attributable to potentially modifiable risk factors, which has led to the notion that targeting these risk factors might reduce the incidence of cognitive decline and dementia. Since sporadic dementia is a multifactorial condition, thought to derive from multiple causes and risk factors, multi-domain interventions may be more effective for the prevention of dementia than those targeting single risk factors. OBJECTIVES: To assess the effects of multi-domain interventions for the prevention of cognitive decline and dementia in older adults, including both unselected populations and populations at increased risk of cognitive decline and dementia. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), and ClinicalTrials.gov on 28 April 2021. We also reviewed citations of reference lists of included studies, landmark papers, and review papers to identify additional studies and assessed their suitability for inclusion in the review. SELECTION CRITERIA: We defined a multi-domain intervention as an intervention with more than one component, pharmacological or non-pharmacological, but not consisting only of two or more drugs with the same therapeutic target. We included randomised controlled trials (RCTs) evaluating the effect of such an intervention on cognitive functioning and/or incident dementia. We accepted as control conditions any sham intervention or usual care, but not single-domain interventions intended to reduce dementia risk. We required studies to have a minimum of 400 participants and an intervention and follow-up duration of at least 12 months. DATA COLLECTION AND ANALYSIS: We initially screened search results using a 'crowdsourcing' method in which members of Cochrane's citizen science platform identify RCTs. We screened the identified citations against inclusion criteria by two review authors working independently. At least two review authors also independently extracted data, assessed the risk of bias and applied the GRADE approach to assess the certainty of evidence. We defined high-certainty reviews as trials with a low risk of bias across all domains other than blinding of participants and personnel involved in administering the intervention (because lifestyle interventions are difficult to blind). Critical outcomes were incident dementia, incident mild cognitive impairment (MCI), cognitive decline measured with any validated measure, and mortality. Important outcomes included adverse events (e.g. cardiovascular events), quality of life, and activities of daily living (ADL). Where appropriate, we synthesised data in random-effects meta-analyses. We expressed treatment effects as risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). MAIN RESULTS: We included nine RCTs (18.452 participants) in this review. Two studies reported incident dementia as an outcome; all nine studies reported a measure for cognitive functioning. Assessment of cognitive functioning was very heterogeneous across studies, ranging from complete neuropsychological assessments to short screening tests such as the mini-mental state examination (MMSE). The duration of the interventions varied from 12 months to 10 years. We compared multi-domain interventions against usual care or a sham intervention. Positive MDs and RRs <1 favour multi-domain interventions over control interventions. For incident dementia, there was no evidence of a difference between the multi-domain intervention group and the control group (RR 0.94, 95% CI 0.76 to 1.18; 2 studies; 7256 participants; high-certainty evidence). There was a small difference in composite Z-score for cognitive function measured with a neuropsychological test battery (NTB) (MD 0.03, 95% CI 0.01 to 0.06; 3 studies; 4617 participants; high-certainty evidence) and with the Montreal Cognitive Assessment (MoCA) scale (MD 0.76 point, 95% CI 0.05 to 1.46; 2 studies; 1554 participants), but the certainty of evidence for the MoCA was very low (due to serious risk of bias, inconsistency and indirectness) and there was no evidence of an effect on the MMSE (MD 0.02 point, 95% CI -0.06 to 0.09; 6 studies; 8697participants; moderate-certainty evidence). There was no evidence of an effect on mortality (RR 0.93, 95% CI 0.84 to 1.04; 4 studies; 11,487 participants; high-certainty evidence). There was high-certainty evidence for an interaction of the multi-domain i
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TL;DR
This Cochrane review assessed whether multi-domain interventions prevent cognitive decline and dementia in older adults, pooling nine RCTs (18,452 participants). It found no evidence of an effect on incident dementia, but a small improvement in cognitive function measured by a neuropsychological test battery, with the strongest effects in trials that included cognitive training.
Key findings
- No evidence of a difference in incident dementia between multi-domain intervention and control groups (RR 0.94, 95% CI 0.76 to 1.18; 2 studies; 7256 participants; high-certainty evidence).
- Small improvement in composite Z-score for cognitive function on a neuropsychological test battery (MD 0.03, 95% CI 0.01 to 0.06; 3 studies; 4617 participants; high-certainty evidence), and on the MoCA (MD 0.76 point, 95% CI 0.05 to 1.46; 2 studies; 1554 participants; very low-certainty evidence).
- No evidence of an effect on MMSE (MD 0.02 point, 95% CI -0.06 to 0.09; 6 studies; 8697 participants; moderate-certainty evidence) or on mortality (RR 0.93, 95% CI 0.84 to 1.04; 4 studies; 11,487 participants; high-certainty evidence).
- High-certainty evidence for an interaction with ApoE4 status on NTB cognitive function (carriers MD 0.14, 95% CI 0.04 to 0.25; noncarriers MD 0.04, 95% CI -0.02 to 0.10; P for interaction 0.09); no clear interaction with baseline MMSE (P for interaction 0.12) or clear effect in those with CAIDE score > 6 (MD 0.07, 95% CI -0.00 to 0.15).
Methods
- Systematic review and random-effects meta-analysis of RCTs; multi-domain intervention defined as more than one component (pharmacological or non-pharmacological), excluding two or more drugs with the same therapeutic target; controls were sham intervention or usual care.
- Searched ALOIS, MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, LILACS, and ClinicalTrials.gov on 28 April 2021; required ≥400 participants and ≥12 months intervention/follow-up.
- Two review authors independently screened, extracted data, assessed risk of bias, and applied GRADE; effects expressed as risk ratios and mean differences with 95% CIs.
Limitations
- Stated: incident dementia conclusions rest on only two trials; cognitive assessment was very heterogeneous (from full neuropsychological batteries to short screening tests); interventions varied in components and intensity; the NTB effect was strongest in trials offering cognitive training, making a learning effect difficult to rule out.
- Stated: MoCA evidence was very low certainty due to serious risk of bias, inconsistency, and indirectness.
- Evident from the text: intervention durations ranged widely (12 months to 10 years), and the review's conclusions on dementia prevention are limited by the small number of trials reporting that outcome.
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“There was no clear evidence for an interaction with baseline cognitive status (defined by MMSE-score) on cognitive function measured with an NTB (low baseline MMSE group MD 0.06, 95% CI 0.01 to 0.11, high baseline MMSE group MD 0.01, 95% CI -0.01 to 0.04, P for interaction 0.12)”
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In the paper
“there was no evidence of an effect on the MMSE (MD 0.02 point, 95% CI -0.06 to 0.09; 6 studies; 8697participants; moderate-certainty evidence)”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“nor was there clear evidence for an effect in participants with a Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score > 6 points (MD 0.07, 95%CI -0.00 to 0.15).”
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In the paper
“We included nine RCTs (18.452 participants) in this review.”
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In the paper
“There was no evidence of an effect on mortality (RR 0.93, 95% CI 0.84 to 1.04; 4 studies; 11,487 participants; high-certainty evidence).”
Strength:plain· not yet calibratedn = 11,487Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“although this effect was strongest in trials offering cognitive training within the multi-domain intervention”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For incident dementia, there was no evidence of a difference between the multi-domain intervention group and the control group (RR 0.94, 95% CI 0.76 to 1.18; 2 studies; 7256 participants; high-certainty evidence).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was high-certainty evidence for an interaction of the multi-domain intervention with ApoE4 status on the outcome of cognitive function measured with an NTB (carriers MD 0.14, 95% CI 0.04 to 0.25, noncarriers MD 0.04, 95% CI -0.02 to 0.10, P for interaction 0.09).”
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In the paper
“We found no evidence that multi-domain interventions can prevent incident dementia based on two trials.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“making it difficult to rule out a potential learning effect”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 2
- The quote only partly states this claim. 1
- Probably not a substantial claim. 7
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and with the Montreal Cognitive Assessment (MoCA) scale (MD 0.76 point, 95% CI 0.05 to 1.46; 2 studies; 1554 participants), but the certainty of evidence for the MoCA was very low (due to serious risk of bias, inconsistency and indirectness)”
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was a small improvement in cognitive function assessed by a NTB in the group of participants receiving a multi-domain intervention”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Interventions were diverse in terms of their components and intensity.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Assessment of cognitive functioning was very heterogeneous across studies, ranging from complete neuropsychological assessments to short screening tests such as the mini-mental state examination (MMSE).”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The duration of the interventions varied from 12 months to 10 years.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Two studies reported incident dementia as an outcome; all nine studies reported a measure for cognitive functioning.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“At least two review authors also independently extracted data, assessed the risk of bias and applied the GRADE approach to assess the certainty of evidence.”
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In the paper
“At least two review authors also independently extracted data, assessed the risk of bias and applied the GRADE approach to assess the certainty of evidence.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“We screened the identified citations against inclusion criteria by two review authors working independently.”
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“At least two review authors also independently extracted data, assessed the risk of bias and applied the GRADE approach to assess the certainty of evidence.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Up to 40% of dementia is attributable to potentially modifiable risk factors.
“Up to 40% of dementia is attributable to potentially modifiable risk factors”
The paper relies on this without support.
Sporadic dementia is a multifactorial condition deriving from multiple causes and risk factors.
“Since sporadic dementia is a multifactorial condition, thought to derive from multiple causes and risk factors”
The paper relies on this without support.
Multi-domain interventions may be more effective for the prevention of dementia than interventions targeting single risk factors.
“multi-domain interventions may be more effective for the prevention of dementia than those targeting single risk factors”
Claims other papers make about this one
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In the citing paper
“A 2021 Cochrane review identified nine multi-domain interventions for the prevention of dementia or cognitive decline RCTs with 18,452 participants.(260)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [260]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“There was high certainty of a small benefit on overall cognition (3 RCTs; composite z score mean difference (MD) 0.03, 0.01- 0.06, n = 4,617, over 18-36 months), (228, 261, 262)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [260]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“particularly in people with the APOE ε 4 genotype (2 RCTs; n = 2,043, follow-up 24-36 months, carriers MD 0.14, 0.04 -0.25, noncarriers MD 0.04, -0.02 to 0.10,)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [260]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Although a UKB study of 300,823 people found that those with cataracts had an increased risk of dementia (HR, 1.2, 1.01 -1.46)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [255]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“but that there was no difference in dementia risk between those who had cataract surgery and healthy controls.(255)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [255]
Experimental — accuracy not yet measured
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Dementia is characterised by progressive cognitive impairment that impacts daily activity, with prevalence in the UK projected to increase to over 2 million by 2051 [3, 4].”
From Do hospital-to-home transitions work for older adults with multiple long-term conditions including dementia? A realist review (2025) · cites this paper as [3]
Experimental — accuracy not yet measured
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Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission
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Izquierdo, M., de Souto Barreto, P., Arai, H., Bischoff-Ferrari, H. A., Cadore, E. L., Cesari, M., Chen, L.-K., Coen, P. M., Courneya, K. S., Duque, G., et al. (2025) · The Journal of nutrition, health and aging · doi:10.1016/j.jnha.2024.100401 · Cited by 273
Metadata
- Authors
- Hafdi, M., Hoevenaar-Blom, M. P., & Richard, E.
- Affiliations
- Amsterdam University Medical Centers (NL)
- Department of Public and Occupational Health; Amsterdam UMC, University of Amsterdam; Amsterdam Netherlands
- Radboud University Nijmegen (NL)
- Venue
- Cochrane Database of Systematic Reviews
- Publisher
- Wiley
- Published
- 2021-11-08
- Volume
- 2021
- Issue
- 11
- ISSN
- 1361-6137 (ISSN-L)
- 1465-1858
- OpenAlex
- W4200308390
- Cited by
- 124
- References
- 128
- Citations by year
- 2026: 21 · 2025: 33 · 2024: 30 · 2023: 27 · 2022: 11 · 2021: 2
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- Locations
- Cochrane Database of Systematic Reviews (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Keywords
- dementia prevention, cognitive decline, multidomain intervention, older adults, mild cognitive impairment, dementia risk factors, lifestyle intervention, cognitive function, incident dementia, mortality, adverse events, cardiovascular events, risk of bias, quality of evidence, citizen science, non-pharmacological treatment, pharmacological interventions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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