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Physical Activity and Exercise in Mild Cognitive Impairment and Dementia: An Umbrella Review of Intervention and Observational Studies

      Abstract

      Objectives

      The aim of this umbrella review was to determine the effect of physical activity/exercise on improving cognitive and noncognitive outcomes in people with MCI (mild cognitive impairment) and dementia.

      Design

      Umbrella review of systematic reviews (SR), with or without meta-analyses (MAs), of randomized controlled trials (RCTs) and observational studies.

      Settings and Participants

      People with MCI or dementia, confirmed through validated assessment measures. Any form of physical activity/exercise was included. As controls, we included participants not following any prespecified physical activity/exercise intervention or following the same standard protocol with the intervention group.

      Methods

      The protocol was registered in PROSPERO (CDR 164197). Major databases were searched until December 31, 2019. The certainty of evidence of statistically significant outcomes was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. SRs' findings, without a formal MA, were reported descriptively.

      Results

      Among 1160 articles initially evaluated, 27 SRs (all of RCTs, 9 without MA) for a total of 28,205 participants with MCI/dementia were included. In patients with MCI, mind-body intervention (standardized mean difference [SMD] = 0.36; 95% confidence intervals [CI] 0.20–0.52; low certainty) and mixed physical activity interventions (SMD = 0.30; 95% CI 0.11–0.49; moderate certainty) had a small effect on global cognition, whereas resistance training (SMD = 0.80; 95% CI 0.29–1.31; very low certainty) had a large effect on global cognition. In people affected by dementia, physical activity/exercise was effective in improving global cognition in Alzheimer disease (SMD = 1.10; 95% CI 0.65–1.64; very low certainty) and in all types of dementia (SMD = 0.48; 95% CI 0.22–0.74; low certainty). Finally, physical activity/exercise improved noncognitive outcomes in people with dementia including falls, and neuropsychiatric symptoms.

      Conclusions and Implications

      Supported by very low-to-moderate certainty of evidence, physical activity/exercise has a positive effect on several cognitive and noncognitive outcomes in people with MCI and dementia, but RCTs, with low risk of bias/confounding, are still needed to confirm these relationships.

      Keywords

      The number of people living with dementia worldwide in 2015 was estimated at 47.5 million, reaching 75.6 million in 2030.
      • Prince M.
      • Guerchet M.
      • Prina M.
      The global impact of dementia 2013–2050.
      Future projections are indicating that this number will be 135.46 million in 2050.
      • Prince M.
      • Guerchet M.
      • Prina M.
      The global impact of dementia 2013–2050.
      Approximately 7.7 million new cases of dementia are anticipated each year.
      • Prince M.
      • Guerchet M.
      • Prina M.
      The global impact of dementia 2013–2050.
      It is widely known that people affected by mild cognitive impairment (MCI) are at greater risk of dementia than the general population, and the annual progression rates range from 10% to 15%.
      • Xue H.
      • Sun Q.
      • Liu L.
      • et al.
      Risk factors of transition from mild cognitive impairment to Alzheimer's disease and death: A cohort study.
      ,
      • Farias S.T.
      • Mungas D.
      • Reed B.R.
      • et al.
      Progression of mild cognitive impairment to dementia in clinic-vs community-based cohorts.
      Unfortunately, there are no curative treatments for dementia or MCI and so epidemiological research regarding risk factors for this disease is of importance. It has been estimated that 3% of dementia cases could be prevented by increasing levels of free-living physical activity
      • Livingston G.
      • Sommerlad A.
      • Orgeta V.
      • et al.
      Dementia prevention, intervention, and care.
      ,
      • Liang J-h
      • Lu L.
      • Li J-y
      • et al.
      Contributions of modifiable risk factors to dementia incidence: A Bayesian network analysis.
      and a growing body of literature is reporting the importance of physical activity and exercise for preventing and eventually slowing down the pathological process and dementia-related problems.
      • Vancampfort D.
      • Solmi M.
      • Firth J.
      • et al.
      The impact of pharmacologic and nonpharmacologic interventions to improve physical health outcomes in people with dementia: A meta-review of meta-analyses of randomized controlled trials.
      In this regard, older people who are physically active are more likely to maintain cognition than those who are not.
      • Livingston G.
      • Sommerlad A.
      • Orgeta V.
      • et al.
      Dementia prevention, intervention, and care.
      In a meta-analysis including 15 prospective cohort studies and 33,816 individuals without dementia at baseline, greater physical activity levels were associated with a significant reduction in the onset of dementia, with high levels of physical activity being the most protective.
      • Sofi F.
      • Valecchi D.
      • Bacci D.
      • et al.
      Physical activity and risk of cognitive decline: A meta-analysis of prospective studies.
      In people already affected by dementia, the important role of physical activity was confirmed; exercise was found to help in improving important outcomes, such as cognition.
      • Panza G.A.
      • Taylor B.A.
      • MacDonald H.V.
      • et al.
      Can exercise improve cognitive symptoms of Alzheimer's Disease?.
      Moreover, physical activity in general and exercise interventions in particular might help in ameliorating behavioral and psychological symptoms in dementia (BPSD).
      • Veronese N.
      • Solmi M.
      • Basso C.
      • et al.
      Role of physical activity in ameliorating neuropsychiatric symptoms in Alzheimer disease: A narrative review.
      However, results are not consistent: a recent large trial has, for example, reported that after a moderate-to-high intensity multicomponent exercise program in people with dementia, intervention group participants performed worse in some cognitive aspects.
      • Lamb S.E.
      • Sheehan B.
      • Atherton N.
      • et al.
      Dementia and Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: Randomised controlled trial.
      The effect of physical activity/exercise in MCI is still not clear. Some studies have reported that physical activity/exercise can prevent the transition from MCI to dementia and that these interventions can improve some cognitive and noncognitive outcomes in this specific population at higher risk for dementia.
      • Nuzum H.
      • Stickel A.
      • Corona M.
      • et al.
      Potential benefits of physical activity in MCI and dementia.
      Given the above, the aim of this umbrella review, promoted by the European Geriatric Medicine Society, is to understand the effect of physical activity/exercise on improving cognitive and noncognitive outcomes in people with MCI/dementia.

      Materials and Methods

      The protocol for this umbrella review is available at: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=164197.

      Literature Search and Inclusion Criteria

      We searched electronic databases MEDLINE/Ovid, PsychINFO, CINHAL, Embase, and Cochrane database for Systematic Reviews from inception to December 31, 2019. We used a combination of MeSH-terms, text words (in title/abstract and keywords) of dementia, MCI, physical activity, and exercise. Full details of the search strategy for MEDLINE/Ovid is reported in Supplementary Table 1. Also, we checked the reference lists of all eligible articles and other relevant narrative articles for possible inclusion.
      Two reviewers (GG, NV) independently searched titles/abstracts for eligibility using https://www.covidence.org/. Any disagreement between reviewers was resolved through discussion and a final agreement was reached. Four authors (NV, DS, JD, PS), in couples, assessed the full-text of those articles retained after the title/abstract screening. Disagreements between reviewers were resolved through discussion and a final agreement was reached.
      • We included the following:
      • (1)
        systematic reviews [SRs] with or without meta-analyses [MAs] of interventions of only randomized controlled trials (RCTs) regarding physical activity/exercise interventions in people with MCI;
      • (2)
        SRs with or without MAs of observational (prospective and case-control) studies comparing people with low physical activity level (versus high level) for the development of dementia in people already affected by MCI;
      • (3)
        SRs with or without MAs of interventions of only RCTs regarding physical activity/exercise interventions in people affected by dementia. We included any form of physical activity (ie, any movement that is carried out by the skeletal muscles that requires energy), as defined by authors. For exercise (ie, a planned, structured, repetitive and intentional movement intended to improve or maintain physical fitness), we included aerobic exercise, resistance exercise, balance and coordination exercise, motor-cognitive interventions (Virtual Reality, Exergaming), mixed programs (eg, aerobic and resistance exercise together), physiotherapy, and physical activity during occupational therapy. As controls, we included participants not following any prespecified physical activity/exercise intervention or following the same standard protocol with the intervention group additionally receiving an exercise/physical activity component.
      When more than 1 SR/MA assessed the same outcome in the same population, we only included the one with the larger number of studies.

      Outcomes

      Primary outcomes: cognitive function explored with validated tests (such as the Mini-Mental State Examination, MMSE
      • Folstein M.F.
      • Robins L.N.
      • Helzer J.E.
      The mini-mental state examination.
      ) and categorized according to global and specific domains (attention, executive function, memory, motor speed, and language);
      • Secondary outcomes:
      • (1)
        incidence of dementia in people with MCI, in observational studies;
      • (2)
        BPSDs, measured with validated tests such as the neuropsychiatric inventory (NPI)
        • Cummings J.L.
        • Mega M.
        • Gray K.
        • et al.
        The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia.
        ;
      • (3)
        adverse events (eg, mortality, falls, fractures, hospitalizations, nursing home admissions);
      • (4)
        medical events (eg, stroke);
      • (5)
        health-related quality of life;
      • (6)
        functional performance tests (eg, gait speed, chair rise, balance, Short Physical Performance Battery [SPPB], aerobic capacity, strength).

      Data Extraction

      Data extraction was led by 2 independent reviewers (JD, GG) and disagreements were resolved through consensus with the senior author (NV). This task proceeded with a 2-step approach. In the first level reported effect sizes (ESs) and the number of studies included in the SR/MA was extracted; in the second level abstraction, this data was confirmed at the single study level.
      We extracted the following data from included studies: the number of studies included, the number of participants in each arm, participant demographics, the length of follow-up, details of physical activity/exercise intervention (type, duration, intensity, frequency), ES of outcomes of interest, heterogeneity, publication bias, conflict of interest.
      Next, the study-specific estimated relative risk for health outcomes was extracted (risk ratio, [RR], odds ratio [OR], hazard ratio [HR], incident risk ratio [IRR], [standardized] mean difference [(S)MD]), along with the 95% confidence interval (CI), and the number of participants for each study by randomization, divided in active intervention and controls. The SMD is used as a summary statistic in meta-analysis when the studies all assess the same outcome using a variety of ways (eg, all studies measure disability, but they use different scales for measuring this characteristic). In this regard, it is necessary to standardize the results of the studies to a uniform scale before combining them.
      • Higgins J.P.
      • Thomas J.
      • Chandler J.
      • et al.
      Cochrane handbook for systematic reviews of interventions.
      The MD is a standard statistic that measures the absolute difference between the mean value between 2 groups and it is commonly used as an effect size when outcome measurements in all studies are made on the same scale.
      • Higgins J.P.
      • Thomas J.
      • Chandler J.
      • et al.
      Cochrane handbook for systematic reviews of interventions.

      Risk of Bias Assessment

      Two reviewers (JD, PS) assessed the risk of bias of the included SRs and MAs using ROBIS (Risk of Bias Assessment Tool for Systematic Reviews). The disagreements were resolved by third reviewer (LS). ROBIS includes 4 different domains: domain 1, study eligibility criteria; domain 2, identification and selection of studies; domain 3, data collection and study appraisal; domain 4, synthesis and findings.

      Data Synthesis and Analysis

      For each meta-analysis, we estimated the summary effect size and its 95% CI by using a random-effects model, with the DerSimonian-Laird's method.
      • IntHout J.
      • Ioannidis J.P.
      • Borm G.F.
      The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.
      Between-study inconsistency was estimated with the I2 metric, with values ≥50% indicative of high heterogeneity.
      • Higgins J.P.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      All statistical analyses were conducted in Stata, version 14.0 (StataCorp, College Station, TX).
      Evidence from meta-analyses of RCTs was assessed in terms of the significance of the summary effect. In case of statistically significant outcomes, we evaluated the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) assessment, that takes in account several important domains in the certainty of the evidence, including study design, risk of bias, inconsistency, indirectness, imprecision and other aspects, such as publication bias.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: An emerging consensus on rating quality of evidence and strength of recommendations.
      The GRADE assessment was made by an investigator (JD) and checked and corrected, if needed, by another reviewer (NV). Supplementary Table 2 reports the criteria used, for each domain, for doing the GRADE, as agreed a priori by 4 investigators (JD, LS, NV, GT). The certainty of the evidence was then reported as: very low (the true effect is probably markedly different from the estimated effect), low (the true effect might be markedly different from the estimated effect), moderate (the true effect is probably close to the estimated effect), or high (there is a lot of confidence that the true effect is similar to the estimated effect).
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: An emerging consensus on rating quality of evidence and strength of recommendations.

      Results

      Literature Search

      As shown in Supplementary Figure 1, 1160 articles were initially included. Of them, 159 full texts were retrieved, with 27 articles finally included (18 MAs and 9 SRs without MA) (reference list in Supplementary Table 3). No observational study on physical activity/exercise in MCI for preventing dementia was included, leaving only RCTs for this umbrella review.

      Descriptive Findings of the Meta-Analyses Included

      Table 1 reports the descriptive findings of the SRs included. Overall, a total of 28,205 participants with MCI/dementia were included, with 14,209 randomized to physical activity/exercise intervention and 13,886 to controls. The physical activity/exercise interventions greatly varied in terms of type, frequency, duration, and intensity across the included SRs, which are fully reported in Table 1. Of importance, in several SRs, poor details regarding the type and the modality of physical activity/exercise were reported.
      Table 1Descriptive Findings of the Studies Included
      Author of the ReviewYearType of ReviewTotal Sample SizeRandomized to Physical Activity/ExerciseRandomized to Control GroupPhysical Activity/Exercise Description (Type, Frequency, Duration, Intensity)

      Intervention
      Outcome Measures
      Adamson2015MA1324662662Physical activity mixed. Mean frequency 3 times per wk; Mean duration 40 min.Depression
      Almeida2019MA1129637492Home-based physical activity. No details regarding mean frequency. duration. intensityThe Mini-Mental Status Examination, Neuropsychiatric Inventory, Alzheimer's Disease Cooperative Study Group ADL scale, Functional Reach test, Timed Up and Go test in people with dementia.
      Barreto2015MA1627622965Physical activity mixed- Mean frequency 3.38 times per wk; Mean duration 38 min.Global BPSD; Mortality
      Brown2019MA524226228Home-based physical activity. No details regarding mean frequency. duration. intensityDisability and Mobility in Alzheimer Disease
      Burge2012MA278126152Physical activity mixed- Mean frequency 2.8 times per wk; Mean duration 36.6 min.Disability in moderate severe dementia
      Burton2015MA336157179Physical activity mixed. No details regarding mean frequency. duration. Intensity.Falls and mean number of falls in dementia
      Cummisuli2017MA768384384Aerobic exercise. Mean frequency 2.55 times per wk; Mean duration 57 min.Cognitive function in MCI
      Cummisuli2018MA554277277Aerobic exercise. Mean frequency 2.57 times per wk; Mean duration 46.25 min.Cognitive function in Alzheimer disease
      Fleiner2017MA20113071Physical activity mixed- Mean frequency 3 times per wk; Mean duration 56 min.BPSD in dementia
      Gates2013MA1695860835Physical activity mixed. Mean frequency 3 times per wk; Mean duration 40 min.TMTB; Digital symbol substitution test; Digit span
      Groot2016MA802433369Physical activity mixed; Mean duration 146 min.Cognitive function in dementia
      Jia2019MA673342331Physical activity mixed; Mean frequency 1.8 times per wk; Mean duration 40 min.Cognitive function in Alzheimer disease
      Leng2018MA228912701019Physical activity mixed. No details regarding mean frequency. duration. intensityDepressive symptoms, BPSD, anxiety, apathy
      Lewis2017MA945306639Home-based physical activity. No details regarding mean frequency. duration. intensityPhysical performance test, falls and hospital readmissions
      Li2019MA20511217834Physical activity mixed. No details regarding mean frequency. duration. intensityDisability (ADL) in dementia
      Lim2019MA325166159Tai Chi. Mean frequency 3 times per wk; Mean duration 46 min.Global cognitive function; Specific cognition
      Ojagbemi2019MA765385380Physical activity mixed- Mean frequency 1 time per wk; Mean duration 130 min.Quality of life
      Packer2019MA338016981682Physical activity mixed- Mean frequency 1.66 times per wk; Mean duration 120 min.Hospitalization; Length of stay in hospital
      Song2018MA929500429Physical activity mixed- Mean frequency 2.45 times per wk; Mean duration 54.5 min.Global cognition; Immediate recall; Delayed memory; Fluency; Stroop
      Wang2019MA1088549539Resistance training; Mean frequency 2.5 times per wk; Mean duration 63 min.Cognitive function in MCI
      Zheng2016MA1587773814Aerobic exercise. Mean frequency 2.28 times per wk; Mean duration 53 min.Immediate recall; Delayed memory in MCI; Attention; Executive function; Fluency
      Zou2019MA940392548Mind-body exercises. Mean frequency 3.8 times per wk; Mean duration 60 min.Cognitive function; Processing speed; Attention; STM; Executive function; Visuospatial executive function
      Bruderer-Hofstetter2018MA1770885885Physical activity mixed. No details regarding mean frequency. duration. intensityDisability in IADL; physical function tests
      Blankevoort2010SR642385257Physical activity mixed. No details regarding mean frequency. duration. intensityStrength, balance, mobility and ADL performance
      Brett2016SR901498403Physical activity mixed. No details regarding mean frequency. duration. intensityHealth and wellbeing in dementia in nursing homes
      Guitar2018SR259127132Physical activity mixed- Mean frequency 2.5 times per wk; Mean duration 129 min.Executive function
      Learner2016SR423202221Physical activity mixed- Mean frequency 3, 4 times per wk; Mean duration 37.5 min.Cognitive function in dementia in nursing homes
      Total28,20514,20913,886
      ADL, Activities of Daily Living; BPSD, Behavioral and Psychological Symptoms in Dementia; IADL, Instrumental activities of daily living; MA, Meta-Analyses; MCI, Mild Cognitive Impairment; SR, Systematic Reviews; STM, Short-term memory; TMTB, Trail Making Test.

      Mild Cognitive Impairment

      Table 1 and Supplementary Table 4 summarize the main findings regarding physical activity/exercise on cognitive function in people affected by MCI. Physical activity/exercise significantly improved global cognition, since mind-body intervention had a small effect on global cognition (SMD = 0.36; 95% CI 0.20–0.52; low certainty according to the GRADE), such as mixed physical activity interventions (SMD = 0.30; 95% CI 0.11–0.49; moderate certainty) and resistance training had a large effect on global cognition (SMD = 0.80; 95% CI 0.29–1.31; very low certainty of evidence). In people with MCI, physical activity/exercise had beneficial effects on attention (SMD = 0.39), executive function (SMD = 0.42), and memory (SMD = 0.26) with a certainty of evidence varying from low to moderate, as fully reported in Table 2 and Supplementary Table 4.
      Table 2Summary of the Main Findings Regarding Cognitive Function of the Meta-analyses Included in the Umbrella Review
      Global CognitionAttentionExecutive FunctionMemoryMotor SpeedLanguage
      MCIMind-body intervention

      Small effect

      Low certainty

      Mixed physical activity intervention

      Small effect

      Moderate certainty

      Resistance training intervention

      Large effect

      Very low certainty
      Mind-body intervention for visuospatial executive function

      Small effect

      Low certainty

      Mind-body intervention

      Small effect

      Low certainty
      Mind-body intervention

      Small effect

      Low certainty
      Mind-body intervention

      Medium effect

      Low certainty

      Tai Chi intervention

      Medium effect

      Low certainty

      Aerobic exercise intervention for delayed memory

      Small effect

      Moderate certainty
      No statistically significant effectNo statistically significant effect
      DementiaMixed physical activity intervention in AD

      Large effect

      Very low certainty

      Mixed physical activity intervention in all dementias

      Medium effect

      Low certainty
      No statistically significant effectNo statistically significant effectNo statistically significant effectNo statistically significant effectNo statistically significant effect
      AD, Alzheimer's disease.
      Finally, in people with MCI, as shown in Table 3 that reports the findings of narrative reviews, mixed physical activity/exercise intervention and aerobic exercise improved physical function and cognitive outcomes, but no effect on disability was observed.
      Table 3Summary of Findings of the Systematic Reviews (Without Meta-analysis) Included
      Author, YearInterventionPopulationOutcomeNumber of StudiesMain Findings
      Cammisuli, 2017Aerobic exerciseADCognitive function8There is scarce evidence that aerobic exercise improves cognition in AD patients. Overall, the included studies reported only positive effects for patients' global cognition after intervention, mainly due to a lack of accurate neuropsychological assessment of each cognitive domain
      Guitar, 2018PA mixedADExecutive function4Significant improvement was seen in all studies.
      Almeida, 2019PA home basedDementiaBPSD7Small effect on BPSD (ES = −0.37, 95% CI −0.57, −0.017)
      Almeida, 2019PA home basedDementiaCarer's burden3Medium reduction on carer's burden (ES = −0.63, 95% CI −0.94, −0.32) for NPI Caregivers subscale and low and negative (ES = −0.45, 95% CI −0.77, −0.13) for ZBI
      Almeida, 2019PA home basedDementiaCognitive function6Medium effect on MMSE (ES = 0.71, 95% CI 0.43, 0.99)
      Almeida, 2019PA home basedDementiaDisability4Important effect on disability (ES = 0.80, 95% CI 0.53, 1.07)
      Almeida, 2019PA home basedDementiaHealth-related physical fitness6Large effect on physical tests Functional Reach test (ES = 2.24, 95% CI 1.80, 2.68), TUG test (ES = −2.40, 95% CI −2.84, −1.96)
      Almeida, 2019PA home basedDementiaQoL2Small effect on QoL
      Blankevoort, 2010PA mixedDementiaPhysical performance test10Lower-limb strength improved equally in multicomponent interventions and progressive resistance training.
      Fleiner, 2017PA mixedDementiaBPSD3All 3 RCTs reported significant reductions of BPSD and differences in comparison to the pre-test and control groups.
      Brown, 2019PA home basedDementia homeDisability7Significant effect of physical activity on functional ability, particularly on mobility items
      Brown, 2019PA home basedDementia homeMobility7Significant effect of physical activity on functional ability, particularly on mobility items
      Brett, 2016PA mixedDementia nursing homeCognitive function7Among 7 RCTs initially included, physical activity improved cognitive measures in two
      Brett, 2016PA mixedDementia nursing homeMood and Depression5Not clear effect on depression and mood measures
      Brett, 2016PA mixedDementia nursing homeFunctional ability5Significant effect of physical activity on functional ability, particularly on mobility items
      Brett, 2016PA mixedDementia nursing homeMobility5Significant effect of physical activity on functional ability, particularly on mobility items
      Learner, 2016PA mixedDementia nursing homeCognitive function5There is moderate-to-strong evidence that physical activity can effectively maintain cognitive function in nursing home residents with Dementia
      BurgePA mixedModerate severe dementiaDisability5In 1 high-quality study over 5, physical activity programs significantly delayed deterioration of ADL performance.
      Bruderer-Hofstetter, 2018PA mixedMCIDisability3In none of the studies, MCT was superior to active comparison or control interventions on IADL performance.
      Bruderer-Hofstetter, 2018PA mixedMCIPhysical performance test4All 3 RCTs reported significant effect of physical activity on balance and physical tests
      Cammisuli, 2017Aerobic exerciseMCICognitive function9There is evidence that aerobic exercise improves cognition in MCI patients. Overall research reported moderate effects for global cognition, logical memory, inhibitory control and divided attention
      AD, Alzheimer's disease; ADL, Activities of Daily Living; BPSD, Behavioral and Psychological Symptoms in Dementia; IADL, Instrumental Activities of Daily Living; ES, Effect Size; MCT, Multicomponent interventions; MMSE, Mini-Mental State Examination; NPI, neuropsychiatric inventory; PA, physical activity; QoL, Quality of Life; TUG, Timed Up and Go; ZBI, Zarit Burden Interview.

      Dementia

      As reported in Table 2 and Supplementary Table 4, in people affected by dementia, mixed physical activity/exercise was effective in improving global cognition in Alzheimer disease (SMD = 1.10; 95% CI 0.65–1.64; very low certainty) and in all types of dementia (SMD = 0.48; 95% CI 0.22–0.74; low certainty), whilst no effect of physical activity/exercise on attention, executive function, memory, motor speed, and language was observed.
      Table 4 summarizes the findings of physical activity/exercise on noncognitive outcomes in people affected by dementia, since no outcome included people with MCI. Home-based physical activity interventions significantly improved disability (SMD = 0.77; 95% CI 0.17–1.37; low certainty of evidence), depressive symptoms (depressive symptoms: SMD = −0.18; 95% CI −0.33 to −0.02; moderate certainty of evidence) and BPSD (MD = −4.62; 95% CI −9.08 to −0.16; very low certainty of evidence). Moreover, physical activity/exercise interventions significantly decreased the risk of falls and the number of falls (MD = −1.06; 95% CI −1.67 to −0.46), with a certainty of evidence low/moderate (Table 4).
      Table 4Effect of Physical Exercise on Noncognitive Outcomes in MCI and Dementia
      Certainty AssessmentNo. of PatientsEffectCertainty
      No. of StudiesRisk of BiasInconsistencyIndirectnessImprecisionOther ConsiderationsPhysical Activity/ExerciseStandard CareRelative (95% CI)Absolute (95% CI)
      Dementia, physical activity interventions home based, activities of daily living
       3Not seriousSerious
      I2 between 50% and 75%.
      Not seriousSerious
      Sample size less than 400 participants.
      None9486-SMD 0.77

      (0.17 to 1.37)


      LOW
      Dementia, physical activity mixed interventions, depressive symptoms
       15Not seriousNot seriousNot seriousNot seriousPublication bias strongly suspected
      Egger's test (P value) <.05.
      707722-SMD −0.18

      (0.33 lower to 0.02 lower)


      MODERATE
      Dementia, physical activity mixed interventions, Behavioral and Psychological Symptoms in Dementia
       6Very serious
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      Very serious
      I2 more than 75%.
      Not seriousNot seriousNone497564-MD −4.62

      (9.08 lower to 0.16 lower)


      VERY LOW
      Dementia, physical activity interventions home based, risk of falls in dementia
       2Not seriousNot seriousNot seriousSerious
      Sample size less than 400 participants.
      Publication bias strongly suspected
      Egger's test (P value) <.05.
      9090RR 0.69

      (0.55 to 0.86)
      -

      LOW
      Dementia, physical activity interventions home based, number of falls in dementia
       3Not seriousNot seriousNot seriousSerious
      Sample size less than 400 participants.
      None134137-MD -1.06

      (1.67 lower to 0.46 lower)


      MODERATE
      Dementia, physical activity mixed interventions, risk of falls
       3Not seriousNot seriousNot seriousSerious
      Sample size less than 400 participants.
      None189182RR 0.69

      (0.55 to 0.85)
      204 fewer per 1000 (from 296 fewer to 99 fewer)

      MODERATE
      I2 between 50% and 75%.
      Sample size less than 400 participants.
      Egger's test (P value) <.05.
      § One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      I2 more than 75%.
      As reported in Table 3, in 2 SRs without meta-analysis involving participants with Alzheimer's disease, aerobic exercise improved only some cognitive outcomes, whilst a mixed physical activity/exercise intervention improved executive function in 4 RCTs. Three SRs reported that mixed and home-based physical activity improved several cognitive (global and specific) and noncognitive (such as BPSD, quality of life, disability, and physical function tests) outcomes in people affected by dementia. These findings are substantially confirmed in people living in nursing home and affected by dementia (Table 4).

      Risk of Bias Assessment in the SRs Included

      Supplementary Figure 2A and B report the evaluation of the risk of bias, according to the ROBIS. Overall, the risk of bias affected more than half of the works included. The most important sources of possible risk of bias were the indication and the selection of the studies.

      Discussion

      In this umbrella review, including 27 articles and 28,205 participants with MCI or dementia, it was found that physical activity/exercise was able to improve cognitive and noncognitive outcomes in RCTs, but the strength of the evidence was overall very low-to-moderate and most SRs included had a high potential risk of bias.
      It is estimated that the prevalence for MCI may range from 18.8% to 28.3% in people ≥ 60 years.
      • Ward A.
      • Arrighi H.M.
      • Michels S.
      • Cedarbaum J.M.
      Mild cognitive impairment: Disparity of incidence and prevalence estimates.
      It is widely known that people affected by MCI are at greater risk of dementia than the general population, and the annual progression rates often range from 10% to 15%.
      • Xue H.
      • Sun Q.
      • Liu L.
      • et al.
      Risk factors of transition from mild cognitive impairment to Alzheimer's disease and death: A cohort study.
      ,
      • Farias S.T.
      • Mungas D.
      • Reed B.R.
      • et al.
      Progression of mild cognitive impairment to dementia in clinic-vs community-based cohorts.
      Among the risk factors that can increase the risk of transition from MCI to dementia, the role of sedentary behavior and physical activity is still poorly explored. For example, in a study including 810 people affected by MCI, it was found that sedentary behavior had no effect on the transition from MCI to dementia.
      • Lu Z.
      • Harris T.B.
      • Shiroma E.J.
      • et al.
      Patterns of physical activity and sedentary behavior for older adults with Alzheimer’s disease, mild cognitive impairment, and cognitively normal in Hong Kong.
      On the contrary, in our umbrella review, physical activity/exercise was able to significantly improve global cognition and specific cognitive tests. However, it should be noted that the evidence was limited by several biases encountered in the RCTs included (eg, small sample size) and some traditionally known limitations in RCTs including older people, such as a potential inclusion bias, confounding by education/social class/brain size/prior cognition.
      • Shenkin S.D.
      • Harrison J.K.
      • Wilkinson T.
      • et al.
      Systematic reviews: Guidance relevant for studies of older people.
      Taken together, these findings suggest a potential role of physical activity/exercise in the prevention or delay in onset of dementia. However, reviews including observational studies exploring the potential role of physical activity/exercise in reducing the rate of the progression for MCI to dementia were not identified when carrying out the present umbrella review.
      In people with dementia, physical activity/exercise was able to improve global cognition, but no specific areas of cognition. It may be hypothesized that the specific areas of cognition are difficult to explore in people with dementia, in particular in advanced stages.
      • Rascovsky K.
      A primer in neuropsychological assessment for dementia.
      Therefore, a floor effect for these tests is expected in more advanced forms of dementia.
      We would like to briefly speculate regarding the possible explanations of our findings, in particular the benefits of physical activity/exercise on cognitive outcomes. First, it is widely known that physical activity/exercise significantly improves the management of cardiovascular risk factors (eg, diabetes, hypertension, dyslipidemia, and obesity) that are traditionally associated to poor cognitive performance.
      • de La Torre J.C.
      Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia.
      Moreover, it is reported that physical activity/exercise may increase neurogenesis and synaptic plasticity.
      • Nuzum H.
      • Stickel A.
      • Corona M.
      • et al.
      Potential benefits of physical activity in MCI and dementia.
      ,
      • Boecker H.
      On the emerging role of neuroimaging in determining functional and structural brain integrity induced by physical exercise: Impact for predictive, preventive, and personalized medicine.
      Physical activity, especially aerobic exercise, is associated with increases in brain-derived neurotrophic factor (BDNF), a factor that can stimulate neuronal cell growth and maintain neurons in good status.
      • Currie J.
      • Ramsbottom R.
      • Ludlow H.
      • et al.
      Cardio-respiratory fitness, habitual physical activity and serum Brain Derived Neurotrophic Factor (BDNF) in men and women.
      Third, using neuroimaging techniques, additional evidence for the impact of physical activity on brain function and structure is reported.
      • Chen L.-Z.
      • Yuan X.
      • Zhang Y.
      • et al.
      Brain functional specialization is enhanced among Tai Chi Chuan practitioners.
      • Lautenschlager N.T.
      • Cox K.
      • Cyarto E.V.
      The influence of exercise on brain aging and dementia.
      • Yue C.
      • Zou L.
      • Mei J.
      • et al.
      Tai Chi training evokes significant changes in brain white matter network in older women.
      In this regard, physical activity/exercise might be a good predictor of long-term changes of brain structure, in particular brain volumes,
      • Valenzuela P.L.
      • Castillo-García A.
      • Morales J.S.
      • et al.
      Exercise benefits on Alzheimer's disease: State-of-the-science.
      and risk for dementia, in particular for those who average more physical activity than their peers.
      • Erickson K.I.
      • Raji C.A.
      • Lopez O.L.
      • et al.
      Physical activity predicts gray matter volume in late adulthood: The Cardiovascular Health Study.
      In addition, physical activity/exercise interventions have an important role in improving several noncognitive outcomes including disability, falls, and neuropsychiatric symptoms in participants affected by dementia. All these outcomes are of clinical importance owing to a high level of co-occurrence and multimorbidity. For example, in one study, the incidence of falls in dementia was 9118 per 1000 person-years significantly higher than in controls.
      • Allan L.M.
      • Ballard C.G.
      • Rowan E.N.
      • Kenny R.A.
      Incidence and prediction of falls in dementia: A prospective study in older people.
      The present umbrella review indicates that physical activity/exercise significantly decreased risk of falls by approximately 31% (equal to an absolute reduction in 204 falls every 1000 people affected by dementia) and also the number of falls (mean one fall over a mean of 6 months of follow-up). Therefore, we hypothesize that the beneficial effect of physical activity/exercise in decreasing the risk of falls and the number of falls may improve activities of daily living (ADL) since these 2 outcomes have been shown to be associated.
      • Gill T.M.
      • Murphy T.E.
      • Gahbauer E.A.
      • Allore H.G.
      Association of injurious falls with disability outcomes and nursing home admissions in community-living older persons.
      Finally, we found that physical activity/exercise may improve depression and BPSD, importantly this finding was also supported by the identified SRs without MA. Specifically, physical activity/exercise was able to significantly reduce 28% of the incidence of depressive symptoms in 15 different RCTs and, similarly, physical activity/exercise significantly reduced the severity of BPSD of 4.62 points on the NPI, which has a score range from 0 to 144. Briefly, we can speculate that physical activity/exercise may improve several aspects strictly related to BPSD, including the production of neurotransmitters, neurotrophins, BDNF, the reduction of oxidative stress and inflammatory levels, increase cerebral blood flow, regulate hypothalamic pituitary adrenal axis, and support of neurogenesis and synaptogenesis.
      • Veronese N.
      • Solmi M.
      • Basso C.
      • et al.
      Role of physical activity in ameliorating neuropsychiatric symptoms in Alzheimer disease: A narrative review.
      However, since this evidence is supported by a very low strength of the evidence, other studies are needed to make stronger these findings.
      This study has limitations that must be taken into consideration when interpreting the findings. First, because the meta-analyses included studies with significant differences in design and population, clinical heterogeneity may have influenced the findings. For example, the present umbrella review does not attempt to identify characteristics of effective interventions and such analyses are beyond the scope of the present study. Future reviews on this topic that attempt to identify successful intervention components are now required. Physical activity/exercise adherence has been assessed using questionnaires, but there are limitations in such measures and objective monitors to record physical activity would provide more reliable estimates. Therefore, the future agenda should envision the use of objective monitors to record physical activity in patients with MCI or dementia, such as accelerometry. Moreover, the MAs included generically reported “dementia” that, on the contrary, can include different diagnoses and different severity. In this regard, the effect of physical activity/exercise in some less prevalent kinds of dementia (eg, Lewy bodies dementia or frontotemporal dementia) should be urgently explored by future RCTs. Furthermore, the literature on exercise training and cognition is characterized by poor quality research and trials, such as single center, small enthusiast led, and poor appreciation of the potential biases. Some recent trials have reported the importance of new technologies for improving physical exercise in people affected by MCI or dementia,
      • Taylor M.E.
      • Close J.C.
      • Lord S.R.
      • et al.
      Pilot feasibility study of a home-based fall prevention exercise program (StandingTall) delivered through a tablet computer (iPad) in older people with dementia.
      but larger RCTs are needed to confirm these findings. Finally, the evaluation of the quality of the included articles indicated that the risk of bias is relatively high for the vast majority.

      Conclusion

      This umbrella review indicated that physical activity/exercise has a positive effect on several cognitive and noncognitive outcomes in people with MCI and dementia. However, these findings are supported by very low-to-moderate certainty of evidence indicating that other RCTs, particularly better structured in terms of physical activity/exercise programs and with larger sample sizes, are needed to fully support the use of physical activity/exercise in patients with MCI or dementia.

      Appendix

      Figure thumbnail fx2
      Supplementary Fig. 2(A, B) ROBIS quality assessment of the included meta-analyses.
      Supplementary Table 1Search Strategy for Medline, Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) 1946 to December 31, 2019 Search Date: 2019–12–31
      #SearchesResults
      1dementia/49095
      2alzheimer disease/90423
      3exp dementia, vascular/6477
      4exp frontotemporal lobar degeneration/4048
      5lewy body disease/3083
      6Cognitive Dysfunction/14399
      7alzheimer∗.kf,tw.141531
      8dementia.kf,tw.105140
      9mild cognitive impairment.kf,tw.15851
      10cognitive decline.kf,tw.20760
      11exp Exercise/186267
      12exp Physical Therapy Modalities/147834
      13Occupational Therapy/12904
      14exercise.kf,tw.255703
      15exergam∗.kf,tw.604
      16physical∗ activ∗.kf,tw.111213
      17physiotherapy.kf,tw.18695
      18physical therapy.kf,tw.20070
      19occupational therapy.kf,tw.10749
      20training.kf,tw.389690
      21"systematic review"/117716
      22meta-analysis/108185
      23(systematic adj1 review).kf,tw.144289
      24meta-analys∗.kf,tw.158520
      25or/1–10243864
      26or/11–20870308
      27or/21–24267732
      2825 and 269695
      2925 and 26 and 271160
      Supplementary Table 2Criteria Evidence for the GRADE
      DowngradeRisk of BiasInconsistencyIndirectnessImprecisionPublication Bias
      −1If 1 or more of the 3 criteria (randomization, masking, dropout rate ≤30%) is not met in 10–30% of trials included in the systematic reviewI2 50–74%The question being addressed by the guideline panel is different from the available evidence regarding the PICO or regarding the characteristics of those who will deliver the intervention(a) The overall number of individuals included in trials is low (less than 400 individuals, both treatment arms) OR (b) the 95% confidence interval includes both 1) no effect and 2) appreciable benefit (RR: ≤0.75) or appreciable harm (RR: ≥1.25)
      For continuous outcomes, “no effect” means an SMD with a confidence interval that crosses zero; appreciable benefit or appreciable harm means that the upper or lower confidence limit crosses an effect size of 0.5 in either direction.
      -
      −2If 1 or more of the 3 criteria (randomization, masking, dropout rate ≥30%) is not met in >30% of trials included in the systematic reviewI2 ≥ 75%The question being addressed by the guideline panel is markedly different from the available evidence regarding the PICO or regarding the characteristics of those who will deliver the intervention(a) the overall number of individuals included in trials is very low (fewer than 400 individuals, both treatment arms) AND (b) the 95% confidence interval includes both 1) no effect and 2) appreciable benefit (RR: ≤0.75) or appreciable harm (RR: ≥1.25)
      For continuous outcomes, “no effect” means an SMD with a confidence interval that crosses zero; appreciable benefit or appreciable harm means that the upper or lower confidence limit crosses an effect size of 0.5 in either direction.
      Egger's test (P value) <.05
      PICO, Population, Intervention, Comparison, and Outcomes.
      For dichotomous outcomes, “no effect” means an estimate with a confidence interval that crosses 1; appreciable benefit or appreciable harm means that the upper or lower confidence limit crosses a risk of 1.25 or 0.75.
      For continuous outcomes, “no effect” means an SMD with a confidence interval that crosses zero; appreciable benefit or appreciable harm means that the upper or lower confidence limit crosses an effect size of 0.5 in either direction.
      Supplementary Table 3List of the References Included in the Umbrella Review
      Blankevoort CG, van Heuvelen MJ, Boersma F, et al. Review of effects of physical activity on strength, balance, mobility and ADL performance in elderly subjects with dementia. Dement Geriatr Cogn Disord 2010;30:392–402.

      Burge E, Kuhne N, Berchtold A, et al. Impact of physical activity on activity of daily living in moderate to severe dementia: a critical review. Eur Rev Aging Phys Act 2012;9:27–39.

      Gates N, Fiatarone Singh MA, et al. The effect of exercise training on cognitive function in older adults with mild cognitive impairment: A meta-analysis of randomized controlled trials. Am J Geriatr Psychiatry 2013;21:1086–1097.

      Adamson BC, Ensari I, Motl RW. Effect of exercise on depressive symptoms in adults with neurologic disorders: A systematic review and meta-analysis. Arch Phys Med Rehabil 2015;96:1329–1338.

      Barreto Pde S, Demougeot L, Pillard F, et al. Exercise training for managing behavioral and psychological symptoms in people with dementia: A systematic review and meta-analysis. Ageing Res Rev 2015;24(Pt B):274–285.

      Burton E, Cavalheri V, Adams R, et al. Effectiveness of exercise programs to reduce falls in older people with dementia living in the community: A systematic review and meta-analysis. Clin Interv Aging 2015;10:421–434.

      Groot C, Hooghiemstra AM, Raijmakers PG, et al. The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials. Ageing Res Rev 2016;25:13–23.

      Zheng G, Xia R, Zhou W, et al. Aerobic exercise ameliorates cognitive function in older adults with mild cognitive impairment: a systematic review and meta-analysis of randomised controlled trials. Br J Sports Med 2016;50:1443–1450.

      Cammisuli DM, Innocenti A, Franzoni F, Pruneti C. Aerobic exercise effects upon cognition in Mild Cognitive Impairment: A systematic review of randomized controlled trials. Archives italiennes de biologie 2017;155:54–62.

      Fleiner T, Leucht S, Forstl H, et al. Effects of short-term exercise interventions on behavioral and psychological symptoms in patients with dementia: A systematic review. J Alzheimers Dis 2017;55:1583–1594.

      Lewis M, Peiris CL, Shields N. Long-term home and community-based exercise programs improve function in community-dwelling older people with cognitive impairment: a systematic review. J Physiother 2017;63:23–29.

      Bruderer-Hofstetter M, Rausch-Osthoff AK, Meichtry A, et al. Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition - A systematic review and network meta-analysis. Ageing Res Rev 2018;45:1–14.

      Cammisuli DM, Innocenti A, Fusi J, et al. Aerobic exercise effects upon cognition in Alzheimer's Disease: A systematic review of randomized controlled trials. Archives italiennes de biologie 2018;156:54–63.

      Guitar NA, Connelly DM, Nagamatsu LS, et al. The effects of physical exercise on executive function in community-dwelling older adults living with Alzheimer's-type dementia: A systematic review. Ageing Res Rev 2018;47:159–167.

      Leng M, Liang B, Zhou H, et al. Effects of physical exercise on depressive symptoms in patients with cognitive impairment: A systematic review and meta-analysis. J Nerv Ment Dis 2018;206:809–823.

      Song D, Yu DSF, Li PWC, Lei Y. The effectiveness of physical exercise on cognitive and psychological outcomes in individuals with mild cognitive impairment: A systematic review and meta-analysis. Int J Nurs Stud 2018;79:155–164.

      Almeida SIL, Gomes da Silva M, Marques A. Home-based physical activity programs for people with dementia: Systematic review and meta-analysis [published online ahead of print December 20, 2019]. Gerontologist.

      Brown SR, Yoward S. The effectiveness of home-based exercise programmes on mobility and functional independence in community-dwelling adults with Alzheimer's disease: a critical review. Int J Ther Rehabil 2019;26:1–14.

      Jia RX, Liang JH, Xu Y, Wang YQ. Effects of physical activity and exercise on the cognitive function of patients with Alzheimer disease: A meta-analysis. BMC Geriatr 2019;19:181.

      Li X, Guo R, Wei Z, et al. Effectiveness of exercise programs on patients with dementia: A systematic review and meta-analysis of randomized controlled trials. Biomed Res Int 2019;2019:2308475.

      Lim KH, Pysklywec A, Plante M, Demers L. The effectiveness of Tai Chi for short-term cognitive function improvement in the early stages of dementia in the elderly: a systematic literature review. Clin Interv Aging 2019;14:827–839.

      Ojagbemi A, Akin-Ojagbemi N. Exercise and quality of life in dementia: A systematic review and meta-analysis of randomized controlled trials. J Appl Gerontol 2019;38:27–48.

      Packer R, Ben Shlomo Y, Whiting P. Can non-pharmacological interventions reduce hospital admissions in people with dementia? A systematic review. PLoS One 2019;14:e0223717.

      Wang S, Yin H, Wang X, et al. Efficacy of different types of exercises on global cognition in adults with mild cognitive impairment: A network meta-analysis. Aging Clin Exp Res 2019;31:1391–1400.

      Zou L, Loprinzi PD, Yeung AS, et al. The beneficial effects of mind-body exercises for people with mild cognitive impairment: a systematic review with meta-analysis. Arch Phys Med Rehabil 2019;100:1556–1573.

      Learner NA, Williams JM. Can physical activity be used to maintain cognitive function in nursing home residents with dementia? A literature review. Phys Ther Rev 2016;21:184–191.

      Brett L, Traynor V, Stapley P. Effects of physical exercise on health and well-being of individuals living with a dementia in nursing homes: A systematic review. J Am Med Dir Assoc 2016;17:104–116.
      Supplementary Table 4Effect of Physical Exercise on Cognitive Outcomes in MCI and Dementia
      Certainty AssessmentNo. of PatientsEffectCertainty
      No. of StudiesStudy DesignRisk of BiasInconsistencyIndirectnessImprecisionOther ConsiderationsPhysical Activity/ExerciseStandard CareRelative (95% CI)Absolute (95% CI)
      Global cognition (in AD) (mixed physical activity intervention)
       13Randomized trialsVery serious
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      Very serious
      I2 ≥ 75%.
      Not seriousNot seriousPublication bias strongly suspected
      Egger's test (P value) <.0001
      342331-SMD 1.10

      (0.65 to 1.64)
      ⊕◯◯◯

      VERY LOW
      Global cognition (in dementia) (mixed physical activity intervention)
       19Randomized trialsNot seriousVery serious
      I2 ≥ 75%.
      Not seriousNot seriousNone433405-SMD 0.48

      (0.22 to 0.74)
      ⊕⊕◯◯

      LOW
      Short-term memory (in MCI) (mind-body intervention)
       12Randomized trialsVery serious
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      Not seriousNot seriousNot seriousNone354389-SMD 0.74

      (0.57 to 0.91)
      ⊕⊕◯◯

      LOW
      Short-term memory (in MCI) (Tai Chi intervention)
       4Randomized trialsVery serious
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      Not seriousNot seriousserious
      Total sample size <400 participants.
      None114240-SMD 0.77 (0.45 to 1.09)⊕◯◯◯

      VERY LOW
      Global cognition (in MCI) (mind-body intervention)
       9Randomized trialsVery serious
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      Not seriousNot seriousNot seriousNone425557-SMD 0.36

      (0.2 to 0.52)
      ⊕⊕◯◯

      LOW
      Executive function (in MCI) (mind-body intervention)
       9Randomized trialsVery serious
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      Not seriousNot seriousNot seriousNone424476-SMD 0.42

      (0.63 lower to 0.21 lower)
      ⊕⊕◯◯

      LOW
      Global cognition (in MCI) (mixed physical activity intervention)
       8Randomized trialsserious
      One or more of the 3 criteria (randomization, masking, dropout rate <30%) is not met in 10% to 30% of trials included.
      Not seriousNot seriousNot seriousNone342334-SMD 0.30

      (0.11 to 0.49)


      MODERATE
      Global cognition (in MCI) (resistance training intervention)
       4Randomized trialsVery serious
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      Serious
      I2 between 50% and 75%.
      Not seriousSerious
      Total sample size <400 participants.
      None7769-SMD 0.80

      (0.29 to 1.31)
      ⊕◯◯◯

      VERY LOW
      Visuospatial executive function (in MCI) (mind-body intervention)
       4Randomized trialsVery serious
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      Not seriousNot seriousNot seriousNone163162-SMD 0.36

      (0.07 to 0.64)
      ⊕⊕◯◯

      LOW
      Delayed memory (in MCI) (aerobic exercise intervention)
       7Randomized trialsNot seriousSerious
      I2 between 50% and 75%.
      Not seriousNot seriousNone638675-SMD 0.26 (0.06 to 0.46)

      MODERATE
      Attention (in MCI) (mind-body intervention)
       5Randomized trialsVery serious
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      Not seriousNot seriousNot seriousNone183182-SMD 0.39

      (0.07 to 0.72)
      ⊕⊕◯◯

      LOW
      One or more of the 3 criteria (randomization, masking, dropout rate >30%) is not met in >30% of trials included.
      I2 ≥ 75%.
      Egger's test (P value) <.0001
      § Total sample size <400 participants.
      ǁ One or more of the 3 criteria (randomization, masking, dropout rate <30%) is not met in 10% to 30% of trials included.
      ∗∗ I2 between 50% and 75%.

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