Front. Public Health Frontiers in Public Health Front. Public Health 2296-2565 Frontiers Media S.A. 10.3389/fpubh.2024.1365589 Public Health Systematic Review Physical activity improves the visual–spatial working memory of individuals with mild cognitive impairment or Alzheimer’s disease: a systematic review and network meta-analysis Deng Jie1 Wang Hong2 Fu Tingting1 Xu Chong3 Zhu Qiqi1 Guo Liya1 Zhu Yu1 * 1College of Physical Education, Southwest University, Chongqing, China 2College of Physical Education and Health Sciences, Chongqing Normal University, Chongqing, China 3Ministry of Sports and National Defense Education, Chongqing College of Electronic Engineering, Chongqing, China

Edited by: Richard Kreider, Texas A&M University, United States

Reviewed by: Omonigho Michael Bubu, New York University, United States

Yi Sub Kwak, Dong-Eui University, Republic of Korea

 *Correspondence: Yu Zhu, zhuyu@swu.edu.cn 28 03 2024 2024 12 1365589 04 01 2024 08 03 2024 Copyright © 2024 Deng, Wang, Fu, Xu, Zhu, Guo and Zhu. 2024 Deng, Wang, Fu, Xu, Zhu, Guo and Zhu

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 Objective

Our network meta-analysis aimed to ascertain the effect of physical activity on the visual–spatial working memory of individuals with mild cognitive impairment and Alzheimer’s disease as well as to propose tailored exercise interventions for each group.

 Methods

Employing a frequentist approach, we performed a network meta-analysis to compare the effectiveness of different exercise interventions in improving the visual–spatial working memory of individuals with mild cognitive impairment and Alzheimer’s disease. Subsequently, we explored the moderating variables influencing the effectiveness of the exercise interventions through a subgroup analysis.

 Results

We included 34 articles involving 3,074 participants in the meta-analysis, comprised of 1,537 participants from studies on mild cognitive impairment and 1,537 participants from studies on Alzheimer’s disease. The articles included exhibited an average quality score of 6.6 (score studies) and 6.75 (reaction time [RT] studies), all passing the inconsistency test (p > 0.05). In the mild cognitive impairment literature, mind–body exercise emerged as the most effective exercise intervention (SMD = 0.61, 95% CI: 0.07–1.14). In Alzheimer’s disease research, aerobic exercise was identified as the optimal exercise intervention (SMD = 0.39, 95% CI: 0.06–0.71).

 Conclusion

The results of the subgroup analysis suggest that the most effective approach to enhancing the visual–spatial working memory of individuals with mild cognitive impairment entails exercising at a frequency of three or more times per week for over 60 min each time and at a moderate intensity for more than 3 months. Suitable exercise options include mind–body exercise, multicomponent exercise, resistance exercise, and aerobic exercise. For individuals with Alzheimer’s disease, we recommend moderately intense exercise twice per week for over 90 min per session and for a duration of 3 months or longer, with exercise options encompassing aerobic exercise and resistance exercise.

 mild cognitive impairment Alzheimer’s disease visual–spatial working memory physical exercise network meta-analysis section-at-acceptance Aging and Public Health Introduction

Baddeley and Hitch (1) have emphasized a central theoretical concept of working memory, which is that working memory is a cognitive mechanism that retains a limited amount of information during an active state to utilize the information in an ongoing task. This definition highlights the role of working memory in a wide range of behaviors and tasks (1). Baddeley has expanded upon the original three-component model proposed in 1974 by introducing an additional subsystem known as the episodic buffer, thereby proposing a comprehensive four-component model of working memory. This extended model comprises the central executive system, visual–spatial sketchpad, episodic buffer, and phonological loop. Positioned at the highest level, the central executive system orchestrates the most intricate executive functions, while the visual–spatial sketchpad, episodic buffer, and phonological loop occupy the second tier, primarily responsible for the transient manipulation of information. Notably, the four-component model underscores the interconnectedness between the phonological loop and visual–spatial sketchpad (2).

The concept of visual–spatial working memory (VSWM) has been proposed by Logie in 1995 and is an important component of working memory, involving the storage and manipulation of spatial information in short-term memory (3). VSWM consists of two elements, visual memory and spatial memory, and is mainly used to temporarily store visual–spatial information (4). VSWM memorizes figures or shapes, and spatial working memory refers to the memory of spatial orientation information and presentation order of objects (5). Simultaneously, research indicates that, compared to the phonological loop, VSWM relies more on central executive functions. This may be a significant factor in visual–spatial working memory, serving as a prominent indicator of cognitive decline.

Mild cognitive impairment (MCI) represents an initial phase of cognitive deterioration characterized by mild deviations in memory, attention, language, and executive functions. Under MCI, these deviations have not yet progressed to a severe level and do not disrupt an individual’s capacity to carry out activities of daily living (6). MCI is characterized by a higher risk of cognitive impairment compared to healthy peers and serves as a crucial early warning signal for the development of Alzheimer’s disease (AD) (6). However, the conversion rate of MCI to AD varies. Follow-up studies have shown that within two to three years, the conversion rate to AD can increase to 50% (7). In a study comparing the VSWM among individuals with MCI and AD and healthy individuals, it has been found that one-fifth of healthy older adults, one-third of individuals with MCI, and half of individuals with AD exhibited visual–spatial working memory impairments (8). They may experience slower memory, lower accuracy, and shorter durations for processing and manipulating spatial information (9). A study on the VSWM of individuals with MCI has found that they display impaired encoding and recognition functions in VSWM tasks, indicating that they may need to exert more effort to maintain their cognitive status (9). Thus, it is necessary to focus on and improve the VSWM of individuals with MCI.

AD is a progressive neurodegenerative disorder and ranks among the most prevalent causes of dementia. The main features of AD are memory loss and a progressive decline in other cognitive functions, including attention, language, spatial orientation, and executive functioning (10). VSWM is mostly associated with the brain’s dorsal pathway, which consists of three pathways that project from the parietal regions to the prefrontal cortex, premotor cortex, and medial temporal lobe regions (11). A disconnection between the ventral and dorsal pathways has been identified in individuals with AD and may potentially play a role in the observed deficits in the VSWM among these individuals (12). Impaired VSWM function resulting from AD may lead to a loss of spatial orientation, an inability to differentiate directions, and even disorientation in familiar environments. As the disease progresses, AD can lead to behavioral and personality changes that affect all aspects of daily life.

Existing research has elucidated the neurophysiological mechanisms underlying the enhancement of working memory in individuals with cognitive impairment through exercise. Specifically, the augmentation of hypothalamic volume through physical exercise has been identified as a significant contributor to memory improvement and the reversal of age-related shrinkage in hypothalamic volume (13). Moreover, physical exercise has been shown to stimulate the generation of new nerve cells, and aerobic exercise induces the expansion of brain tissue, leading to increased gray and white matter in crucial cognitive regions, such as the prefrontal cortex (14, 15). This collective evidence underscores the multifaceted impact of physical exercise on cognitive function in individuals with cognitive impairment, offering insights into its neurobiological underpinnings.

Previous research has confirmed the beneficial effects of physical exercise on the VSWM of individuals with MCI and AD (16–19). Relevant meta-analyzes and experimental studies have discussed overall cognitive function, working memory, and executive function (20, 21). These studies’ intervention programs include aerobic (22), resistance (23), multicomponent (24), and mind–body exercises (25), and different intensities (low-intensity, moderate-intensity, and high-intensity) (26) have been examined. Additionally, these studies examine the impact of exercise on the VSWM of healthy individuals (27), with particular emphasis on its effects in children (28). However, research on the effects of exercise interventions on the VSWM of individuals with different stages of cognitive impairment is limited. As an important marker of cognitive decline, VSWM needs to be monitored and improved at different stages of cognitive impairment. Does exercise produce improvements in VSWM of individuals with different stages of cognitive impairment? Which physical exercise programs offer the best improvement of VSWM in individuals with MCI and AD? These questions are the focus of our study.

Therefore, our systematic review aims to investigate the impact of exercise on VSWM in individuals with MCI and AD separately. Additionally, a comprehensive net meta-analysis will be undertaken, grounded in the initial meta-analysis, to furnish quantitative evidence regarding the enhancement of the VSWM of individuals with MCI and AD. This will be achieved by directly or succinctly contrasting various physical activity regimens through the net meta-analysis, thereby facilitating the visualization of comparative outcomes (29). Furthermore, the optimal physical activity regimen will be discerned through a systematic ranking process, contributing to a refined understanding of the potential benefits of exercise on the VSWM of individuals with MCI and AD.

 Materials and methods

We have registered the protocol for this systematic review on PROSPERO (CRD42023459625). The network meta-analysis followed the PRISMA extension statement for systematic reviews reporting on network meta-analyzes (30).

Eligibility criteria

Two authors (JD and TTF) conducted the initial screening of studies. Our meta-analysis included studies meeting the following criteria: (1) Participants had been diagnosed with MCI or AD, regardless of age. (2) Participants had either normal vision or vision corrected through aids. (3) The intervention involved a distinct form of physical activity, satisfying two conditions: skeletal muscle movement and energy expenditure. (4) All outcomes were quantified using validated measurement tools, encompassing both voluntary physical and mental strength. (5) We exclusively considered randomized controlled trials (RCTs) due to their providing the highest level of evidence in meta-analyzes. We excluded reports that did not meet the following criteria: (1) The publication was not in English or Chinese. (2) The full text or essential data (such as means and standard deviations) were unavailable.

 Information sources

We conducted a prospective search on September 15, 2023, utilizing WoS, MEDLINE, BIOSIS Previews, PubMed, the China National Knowledge Infrastructure (CNKI), and Wanfang Data (Chinese) databases to find relevant papers. Due to limited human resources, only six databases with RCTs were chosen for this review. To determine inclusion, we simultaneously reviewed all included study citations. We consulted the study’s corresponding author when needed.

 Search strategy

A systematic search strategy was applied using a MeSH word search. For example, the following forms of retrieval were employed: “Mild cognitive impairment” [MeSH] (e.g., “Mild cognitive impairment” OR “Cognitive Dysfunctions” OR “Dysfunction, Cognitive” OR “Cognitive Impairments” OR “Impairment, Cognitive” OR “Cognitive Disorder” OR “Cognitive Disorders” OR “Disorder, Cognitive” OR “Disorders, Cognitive” OR “Mild Cognitive Impairment” OR “Cognitive Impairment, Mild” OR “Cognitive Impairments, Mild” OR “Impairment, Mild Cognitive” OR “Impairments, Mild Cognitive” OR “Isometric Exercises” OR “Mild Cognitive Impairments” OR “Cognitive Decline” OR “Mental Deterioration” OR “Decline, Cognitive” OR “Deterioration, Mental” OR “Deterioration, Mental” OR “Mental Deterioration”) AND “Alzheimer’s disease” [MeSH] (e.g., “Alzheimer Dementia” OR “Alzheimer Dementias” OR “Dementia, Alzheimer” OR “Alzheimer’s Disease” OR “Senile Dementia”) AND “Cognition” [MeSH] (e.g., “Cognitions” OR “Cognitive Function” OR “Cognitive Functions” OR “Function, Cognitive” OR “Functions, Cognitive”) AND “Memory, Short-Term” [MeSH] (e.g., “Memories, Short-Term” OR “Short-Term Memories” OR “Memory, Short term” OR “Memories, Short term” OR “Working Memory” OR “Working Memories” OR “Immediate Memories” OR “Immediate Memory” OR “Memories, Immediate” OR “Recalls, Immediate”).

 Study selection

We loaded all main database articles into EndNote to remove duplication. JD and TTF separately retrieved research design, efficacy, and safety data using a structured spreadsheet. If the two reviewers disagreed, a third author decided after reviewing the article. To assure inter-author agreement, JD and TTF individually completed the eligibility evaluation for study inclusion in an unblinded, standardized manner in a pilot test before the official commencement. This allowed us to resolve disagreements by consensus. The main information extracted included (1) basic information, such as author(s) and the year of publication; (2) participant characteristics, such as physical condition (healthy people or those with medical conditions), the mean age or age range of the experimental and control groups, and the sample size; and (3) experimental characteristics such as study design, type of intervention, type of control, information about the intervention (duration of each intervention session and the duration, frequency, and intensity of the intervention), measurement tools, and outcome indicators. One author (TF) extracted important data from the articles’ full texts, abstracts, tables, and charts or Supplementary material. The relevant authors were contacted for missing data for analysis. Second author JD reviewed extracted data.

 Risk of bias assessment

Two authors (JD and TTF) conducted independent assessments of the risk of bias within the included studies using the Physical Therapy Evidence Database (PEDro) scale (31). This scale comprises 11 items: eligibility criteria, randomization, concealed allocation, similarity at baseline, blinding of subjects, therapists and assessors, retention rate exceeding 85%, intention-to-treat analysis, between-group comparisons, point measures, and measures of variance. The total quality assessment score, derived from the scores of 10 criteria (excluding the first item, eligibility criteria), ranges from 0 to 10. Per Maher et al. (30) criteria, a score of ≥6 indicates that the assessed study is of high quality, while a score of <6 suggests low quality. Any discrepancies or disagreements between the reviewers were resolved through consultation with a third reviewer (YZ).

 Statistical synthesis and analysis

A meta-analysis compared exercise programs to controls. A random-effects model which included a 95% CI and the SMD for each research computed the standardized mean difference (SMD). The I2 statistic with a 95% CI was used to quantify heterogeneity, with thresholds of 0, 25, 50, and 75% indicating absent, low, moderate, and high study inclusion.

The type of exercise and dose parameters may affect the extent of cognitive impact and the duration of these effects post-intervention (32). We explore the optimal exercise regimen based on the FITT principle, which considers frequency, intensity, time, and type (33). Subgroup analyzes were conducted on four moderating variables: exercise intervention intensity was categorized into three levels: low, moderate, and high, supported by research; changes in neurobiological factors induced by exercise may be dose-dependent on exercise intensity (34). The determination of exercise intensity followed the range Borer has proposed, where less than 50% of the maximum oxygen (V02max) consumption is considered low intensity, 50 to 75% is moderate intensity, and more than 75% is high intensity (35). If not explicitly reported in the article, intensity was determined based on principles of physiology and exercise science. The exercise intervention duration was divided into three subgroups: <60 min, 60–89 min, and ≥ 90 min. Although animal model research has suggested that exercise intervention duration influences the corresponding working memory enhancement, its applicability to MCI and AD remains inconclusive (36). Intervention duration was categorized into three groups: <90 days, 90–179 days, and ≥ 180 days. Does a prolonged exercise regimen yield superior effects on VSWM? Is there an optimal effect size? These questions require further subgroup analysis. Weekly intervention frequency was subdivided into three categories: less than twice per week, three to four times per week, and five or more times per week. Is there a correlation between weekly intervention frequency and improvements in MCI and AD through exercise? To answer these questions, an exploration of the optimal intervention frequency is warranted.

A network meta-analysis was conducted using Stata 15.1 within a frequentist framework. The network analysis incorporated the results of each study, including direct comparisons and network evidence from RCTs. We categorize exercise interventions into the following types: aerobic exercise (Walking, cycling, treadmill, etc.), mind–body exercises (combining aerobic exercise with cognitive training, Tai Chi, yoga etc.), multicomponent exercise (involving three or more types of exercise), resistance training (resistance band exercises etc.), acute exercise, and finger exercises. A network graph containing intervention measures at each node was created by comparing each intervention to a common comparator. Lines connecting nodes indicated direct RCT intervention measure comparisons. More research used direct comparisons with thicker lines. The node size indicated how many people received an intervention. Clinical and other factors can cause study heterogeneity, hence a random-effects model was adopted. This method yields conservative CIs.

To evaluate the heterogeneity between the studies, an inconsistency analysis was performed. Inconsistency test p-values above 0.05 were analyzed using a consistency model. Exercise interventions were ranked using cumulative ranking curve area (SUCRA) and mean rankings. SUCRA accurately estimates the cumulative ranking probability for top-i treatments.

 Risk of publication bias

Our research assessed publication bias by assessing the standard error and its reciprocal for each article. For dispersion visualization, a funnel plot was created. Visual inspection and Egger’s test showed no publication bias because the funnel plot was symmetrical. In order to eliminate publication bias, Begg’s test, an adjusted rank correlation test, was performed.

 Results Description of the included studies

Initially, 382 articles were included after deleting duplicates and screening titles and abstracts. After applying inclusion and exclusion criteria, this study included 34 articles, 23 of which included MCI individuals and 11 with AD patients. The study involved a total of 3,074 participants, including 1,537 individuals with MCI and 1,537 with AD (Figure 1). Among the 23 MCI studies, there were 27 experiments in total, with eight experiments investigating the effects of aerobic exercise (AE), seven studying the effects of resistance exercise (RE), seven examining the effects of multicomponent exercise (ME), three exploring the effects of mind–body exercise (MBE), one focusing on the effects of finger exercises (FINGER), and one investigating the effects of acute exercise (ACUTE). Notably, five experiments directly compared different exercise interventions, with two employing a three-arm design. Among the 11 AD articles, there were 18 experiments in total, including five exploring the effects of AE, six assessing the effects of RE, and five studying the effects of ME. Two of these experiments directly compared different exercise interventions, both utilizing a three-arm design. Table 1 shows the articles selected for web-based meta-analysis.

Selection of studios for inclusion.

Characteristics of the studies included in the meta-analysis.

Reference Country Individual characteristics Group Intervention type Control type Intervention characteristics Measuring tool Outcomes measurement
Yoon et al. (37) Korea Older adults with MCI, n = 43Female = 30 (69.8%)EG age: 73.82 ± 4.37CG age: 74.03 ± 4.27 EG: n = 20CG: n = 23 Resistance exercise DR, S 16 weeks3 session/week60 min/session ①②⑥ Score
Gavelin et al. (38) Sweden Persons with exhaustion disorder, n = 132Female = 111 (84%)EG-a age: 43.89 ± 9.21EG-b age: 44.15 ± 8.60CG age: 41.88 ± 7.41 EG-a: n = 44EG-b: n = 47CG: n = 41 Aerobic exerciseCognitive training NM 12 weeks3 session/week40 min/session ①② Score
Li et al. (39) Hong Kong, China Persons with MCI, n = 229Female = 196 (85.6%)EG age: 73.93 ± 7.40CG age: 74.83 ± 7.57 EG: n = 116CG: n = 113 Multicomponent training:Aerobic exerciseResistance exerciseBalance exerciseFlexibility exercise NM 8 weeks3 sessions/week60 min/session ①② Score
Eskilsson et al. (40) Sweden Persons with exhaustion disorder, n = 56Female = 52 (92%)EG age: 42.00 ± 8.61CG age: 41.69 ± 7.88 EG: n = 24CG: n = 32 Aerobic exercise CT 12 weeks3 session/week40 min/session ①② Score
Dannhauser et al. (41) United Kingdom Persons with MCI, n = 67Female = 28 (42%)Age: 73.9 ± 8.3 NR Aerobic exerciseCognitive training NR 12 weeks3 session/week30–45 min/session ①②⑥ Score
Devenney et al. (42) Ireland Persons with MCI, n = 64Female = 34 (53.2%)EG age: 71.7 ± 5.3CG age: 69.0 ± 7.2 EG: n = 35CG: n = 29 Acute high-intensity Aerobic exercise NR 12 weeks90 min/session ⑤ Score
Hong et al. (43) Korea Persons with MCI, n = 22Female = 16 (73%)Healthy persons, n = 25Age: 75.53 ± 4.48 EG-MCI: n = 10CG-MCI: n = 12EG-NG: n = 12CG-NG: n = 13 Resistance exercise DR 12 weeks2 sessions/week60 min/session ①② Score
Suzuki et al. (24) Japan Older adults with MCI, n = 100Female = 49 (49%)EG age: 74.8 ± 7.47CG age: 75.8 ± 6.1 EG: n = 50CG: n = 50 Aerobic exercise Muscle strength trainingPostural balance retrainingDual-task training CT 6 months2 sessions/week90 min/session ⑧ Score
Scherder et al. (44) The Netherlands Frail older adults with MCI, n = 43Female = 38 (88%)EG-a age: 84 ± 6.38EG-b age: 89 ± 2.40CG age: 86 ± 5.05 EG-a: n = 15EG-b: n = 13CG: n = 15 Hand/face exercisesAerobic exercise NM 6 weeks3 sessions/week30 min/session ④⑨ Score
Nagamatsu et al. (45) Canada Women with subjective memory, n = 86EG-a age: 73.9 ± 3.4EG-b age: 75.6 ± 3.6CG age: 75.1 ± 3.6 EG-a: n = 28EG-b: n = 30CG: n = 28 Resistance exerciseAerobic exercise Balance and tone 6 months2 sessions/week ⑩⑪ Score
Jeong et al. (46) Korea Female = 18 (69%)EG age: 70.23 ± 7.47CG age: 71.77 ± 5.53 EG: n = 13CG: n = 13 Aerobic exercisePA promotionBehavior modificationCognitiveExercise multi-task programs DR 12 weeks2 sessions/week90 min/session ⑥ Score
Avenali et al. (47) Italy Older adults with amnestic MCI, n = 31Female = 26 (84%)EG age: 72.88 ± 5.60CG age: 77.29 ± 5.16 EG: n = 17CG: n = 14 Aerobic exercises, coordination exercises, Physical therapy 12 weeks2 sessions/week60 min/session ⑥ Score
Suzuki et al. (48) Japan Older adults with MCI, n = 50Female = 23 (46%)EG age: 75.3 ± 7.5CG age: 76.8 ± 6.8 EG: n = 25CG: n = 25 Aerobic exerciseMuscle strengthtrainingPostural balance retraining CT 12 months2 sessions/week90 min/session ⑦⑫ Score
Yang et al. (49) China Older adults with non-dementia cognitive impairment after stroke, n = 91Female = 39 (43%)EG age: 74.6 ± 5.5CG age: 73.4 ± 5.8 EG: n = 46CG: n = 45 Resistance trainingAerobic training CT\W 3 months4 sessions/week20 min/session ⑰ Score
Wang and Sheng (50) China Older adults with MCI, n = 94NRAge: 77.1 ± 4.3 EG: n = 46CG: n = 48 Tai Chi CT 6 months4 sessions/week40 min/session ⑥ Score
Lam et al. (51) Hong Kong, China Persons with mild dementia, n = 376Female = 301 (80%)EG-a age: 79.8 ± 6.4EG-b age: 80.3 ± 6.2EG-c age: 80.7 ± 7.0CG age: 80.8 ± 6.3 EG-a: n = 94EG-b: n = 94EG-c: n = 94CG: n = 94 Working memory trainingPhysical exerciseCombined working memory and physical exercise CT 6 weeks2 sessions/week45 min/session ① Score
van de Rest et al. (52) The Netherlands Frail and pre-frail older adults, n = 127Female = 102 (80.3%)Age:≥65 years EG-a: n = 31CG-a: n = 34EG-b: n = 31CG-b: n = 31 Resistance-type exercise training in combination with protein supplementation Resistance-type exercise 24 weeks2 sessions/week ①②⑥ Score
Makino et al. (53) Japan Older adults with SMC, n = 415Female = 195 (47%)EG-AT age: 72.25 ± 4.56EG-RT age: 72.33 ± 4.77EG-CT age: 72.61 ± 4.52CG age: 72.10 ± 4.61 EG-AT: n = 104EG-RT: n = 102EG-CT: n = 104CG: n = 105 Aerobic exerciseResistance exerciseCombined exercise NR 26 weeks2 sessions/week60 min/session(a total of 52 sessions) ① Score
Barnes et al. (54) United States Older adults with mild dementia, n = 63Female = 41 (65%)EG age: 64–81.2CG age: 74.7–82.2 EG: n = 32CG: n = 31 Treadmill training NM 16 weeks2 sessions/week30 min/session ①②④⑤⑥ Score
Hoffmann et al. (55) Denmark Persons with mild AD, n = 200Female = 87 (43.5%)EG age: 69.8 ± 7.4CG age: 71.3 ± 7.3 EG: n = 107CG: n = 93 Moderate-to-high intensity aerobic exercise NM 16 weeks3 sessions/week60 min/session ⑤ Score
Bossers et al.(56) The Netherlands Persons with dementia, n = 109Female = 82 (75%)Age: 85.5 ± 5.1 EG-a: n = 37EG-b: n = 36CG: n = 36 Aerobic and strength training CT\NM 9 weeks2 sessions/week30 min/session ⑱ Score
Cheng et al. (57) Hong Kong, China Persons with MCI, n = 110Female = 67 (60.9%)EG-m age: 81.9 ± 6.2EG-t age: 81.8 ± 7.4CG age: 80.9 ± 7.2 EG-m: n = 36EG-t: n = 39CG: n = 35 MahjongTai Chi CT 12 weeks3 sessions/week ①② Score
Yu et al. (58) United States Older adults with AD dementia, n = 96Female = 43 (45%)EG age: 77.4 ± 6.6CG age: 77.5 ± 7.1 EG: n = 64CG: n = 32 Cycling S 6 months3 sessions/week20–50 min/ session ⑭ Score
Huang et al. (59) China Older adults with mild dementia, n = 80Female = 56 (67.5%)EG age: 81.9 ± 6.0CG age: 81.9 ± 6.1 EG: n = 40CG: n = 40 Tai Chi NM 10 months3 sessions/week20 min/session ⑥ Score
Lautenschlager et al. (60) Australia Persons who reported memory problems but did not meetcriteria for dementia, n = 170Female = 86 (50.5%)EG age: 68.6 ± 8.7CG age: 68.7 ± 8.5 EG: n = 85CG: n = 85 Aerobic exercise NM 3 sessions/week50 min/session ④ Score
Cavalcante et al. (61) Brazil Older adults with cognitiveFemale = 47 (62.6%)complaints, n = 67EG-a age: 71 (6)EG-b age: 71 (6)CG age: 71 (4) EG-a: n = 23EG-b: n = 22CG: n = 22 Resistance exercise CT 12 weeks3 sessions/week ④ Score
Prick et al. (62) The Netherlands Persons with dementia and theirfamily caregivers, n = 111Female = 41 (36.9%)Minimum age of 55 years EG: n = 57CG: n = 54 FlexibilityStrengtheningBalanceEndurance NM 3 months3 sessions/week30 min/session ①②⑮ Score
Sanders et al. (63) The Netherlands Persons with dementia, n = 91Female = 43 (62.3%)EG age: 81.7 (7.16)CG age: 82.1 (7.51) EG: n = 39CG: n = 30 Aerobic sessionsLower limb strength exercises CT\S 24 weeks3 sessions/week30 min/session ①②⑥⑦⑯ Score
Pedroso et al. (64) Brazil Older adults with diagnosis of AD, n = 57Female = 44 (77.1%)EG-a age: 77.6 ± 6.2EG-b age: 78.0 ± 5.6CG age: 79.2 ± 5.6 EG-a: n = 22EG-b: n = 21CG: n = 14 Aerobic enduranceFlexibilityMuscular resistanceBalance NM 12 weeks3 sessions/week60 min/session ①②⑥ Score
Stein et al. (65) Brazil Persons with AD, n = 34Female = 19 (56%)EG age: 75.27 ± 6.09CG age: 75.06 ± 6.36 EG: n = 18CG: n = 16 Aerobic training DR 12 weeks3 sessions/week60 min/session ⑰ Score
Liao et al. (66) Taiwan, China Frail older adults, n = 46Female = 31 (67.3%)EG age: 79.6 (9.0)CG age: 83.8 (5.1) EG: n = 25CG: n = 21 Kinect based exergaming Combined physicalexercise 12 weeks3 sessions/week60 min/session ③⑥ RT
Law et al. (67) Australia Older adults with MCI, n = 83Female = 50 (60.2%)EG age: 60–85/73.68 (6.8)CG age: 60–88/74.1 (7.6) EG: n = 43CG: n = 40 FcTSim program CT 13 sessions in 10weeks ⑥ RT
Thaiyanto et al. (68) Thailand Older women with MCI, n = 40EG age: 67.66 ± 2.38CG age: 68.13 ± 2.65 EG: n = 20CG: n = 20 Aerobic exerciseResistance exerciseBalance exercise DR 12 weeks3 sessions/week60 min/session ⑥ RT
Law et al. (69) Australia Older adults with MCI, n = 59Female = 35 (50.7%)EG-a age: 62–86/76.93 (6.79)EG-b age: 68–88/77.94 (6.11)EG-c age: 64–85/71.57 (7.43)CG age: 60–89/75.14 (8.53) EG-a: n = 15EG-b: n = 16EG-c: n = 14CG: n = 14 Cognitive trainingAerobic exercise DR 8 weeks12 sessionsmore than 40 min ⑥ RT

MCI, mild cognitive impairment; AD, Alzheimer’s disease; NR, Not reported; EG-a: Experimental group a; EG-b, Experimental group b; EG-c, Experimental group c; CG-a, Control group a; CG-b, Control group b, RCT, randomized controlled trial; NM, No movement; CT, Cognitive training; DR, Daily routine; S, Stretching; R, Reading; PC, Passive cycling; W, Walk; ① digits span backward; ② digits span forward; ③ N-back; ④ DS: Digits span; ⑤ Stroop; ⑥ TMT; ⑦Stroop color and word test; ⑧ Wechsler memory scale; ⑨ Visual–spatial working memory; ⑩ Reaction time for spatial memory by a computerized task; ⑪ Accuracy for spatial memory by a computerized task; ⑫ Logical memory subtest of the Wechsler memory scale-revised; ⑬ Memory composite; ⑭ ADAS-Cog; ⑮ 8 words test; ⑯ Visual memory span backward; ⑰ Clock drawing test; ⑱ Visual memory span forward.

 Risk of bias

The overall publication bias in the literature for both MCI and AD was evenly distributed in the funnel plot and approximately symmetrical (Figure 2A). When relevant, Begg’s and Egger’s tests were used to assess publication bias in the systematic review, which demonstrated no publication bias overall for both MCI (p = 0.769 > 0.1) and AD (p = 0.085 > 0.05). Furthermore, in the MCI section, we assessed the publication bias of the studies using scores and reaction time as the outcome measures separately; the results showed no publication bias in either the reaction time studies (p = 0.886 > 0.1) or score studies (p = 0.238 > 0.1).

Funnel plot of publication bias. (A) MCI-Score. (B) MCI-RT. (C) AD.

 Methodological quality evaluation

Quality evaluation of the 34 included articles was conducted utilizing the PEDro scale (Table 2). The mean score for studies using scores as the outcome measure was 6.6, whereas the mean score for studies using reaction time as the outcome measure was 6.75. Furthermore, all articles included in the analysis had conducted “between-group statistical analyzes” and had furnished “point measures and measures of variance.” Of these articles, 30 utilized random assignment for experimental grouping, 28 detailed the process of random assignment, 32 provided information about the baseline levels of participants, 32 presented primary outcome measures for more than 85% of participants, and 32 reported a retention rate and completeness of measurements exceeding 85%.

PEDro scores and sum of the included studies.

Articles Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 8 Item 9 Item 10 Item 11 Sum (Items 2–11)
Score
Yoon et al. (33) 1 1 0 1 0 0 0 1 1 1 1 6
Gavelin et al. (34) 1 1 0 1 0 0 0 1 1 1 1 6
Li et al. (35) 1 1 0 1 0 0 1 1 1 1 1 7
Eskilsson et al. (36) 1 1 0 1 0 0 0 1 1 1 1 6
Dannhauser et al. (37) 1 1 0 1 0 0 0 0 1 1 1 5
Devenney et al. (38) 1 1 0 1 0 0 0 1 1 1 1 6
Hong et al. (39) 1 1 0 1 0 0 0 1 1 1 1 6
Suzuki et al. (23) 1 1 0 1 0 0 1 1 1 1 1 7
Scherder et al. (40) 1 1 0 1 0 0 1 1 1 1 1 7
Nagamatsu (41) 1 1 1 1 0 0 1 1 1 1 1 8
Jeong et al. (42), Sanders et al. (58) 1 1 0 1 0 0 0 1 1 1 1 6
Avenali et al. (43) 1 1 1 1 0 0 1 1 1 1 1 8
Suzuki et al. (24) 1 1 0 1 0 0 0 1 1 1 1 6
Yang et al. (44) 1 0 0 1 0 0 0 1 1 1 1 5
Wang and Sheng (45) 1 1 0 1 0 0 0 1 1 1 1 6
Lam et al. (46) 1 1 0 1 0 0 0 1 1 1 1 6
van de Rest et al. (47) 1 1 0 1 1 1 0 1 1 1 1 8
Makino et al. (48) 1 1 1 1 0 0 1 1 1 1 1 8
Barnes et al. (49) 1 1 0 1 0 0 1 1 1 1 1 6
Hoffmann et al. (50) 1 1 0 1 1 1 1 1 1 1 1 9
Bossers et al. (51) 1 1 0 1 0 0 0 1 1 1 1 6
Cheng et al. (52) 1 1 0 1 0 0 0 1 1 1 1 6
Yu et al. (53) 1 1 0 1 0 0 0 1 1 1 1 6
Huang et al. (54) 1 1 0 1 0 0 1 1 1 1 1 7
Lautenschlager et al. (55) 1 1 1 1 0 0 1 1 1 1 1 8
Cavalcante et al. (56) 1 1 0 1 1 0 1 1 1 1 1 8
Prick et al. (57) 1 1 1 1 0 1 0 1 1 1 1 8
Sanders et al. (58) 1 0 0 1 0 0 0 1 1 1 1 5
Pedroso et al. (59) 1 1 0 1 0 0 1 1 1 1 1 6
Stein et al. (60) 1 1 0 1 0 0 0 1 1 1 1 6
Mean (Score) 6.6
Reaction time (RT)
Liao et al. (61) 1 1 0 1 0 0 1 1 1 1 1 7
Law et al. (62) 1 1 1 1 0 0 1 1 1 1 1 6
Thaiyanto et al. (63) 1 1 0 1 0 0 1 1 1 1 1 7
Law et al. (64) 1 1 0 1 0 0 1 1 1 1 1 7
Mean (RT) 6.75

Item 1: eligibility criteria; Item 2: randomization; Item 3: concealed allocation; Item 4: similar baseline; Item 5: blinding of subjects; Item 6: blinding of therapists; Item 7: blinding of assessors; Item 8: more than 85% retention; Item 9: intent-to-treat analysis; Item 10: between-group comparison; Item 11: point measures and measures of variability.

 Meta-analysis results Heterogeneity test

Twenty-three articles report on physical activity’s effect on the VSWM of individuals with MCI, with 15 using scores as the outcome measure and 8 using reaction time. Results for heterogeneity show that the choice of outcome measures may be a source of heterogeneity: I2 = 50.6%, p < 0.001 for studies related to scores, and I2 = 0.00%, p < 0.001 for studies related to reaction time (Table 3). The heterogeneous results suggest that other outcome measures may contribute to heterogeneity; hence, independent analyzes were performed for each. Eleven articles examine physical activity’s effect on the VSWM of individuals with AD, using scores as the measure of outcome. The heterogeneity test results showed that I2 = 62.9%, p < 0.001 (Table 3).

Heterogeneity analysis of exercise effects of included studies.

Heterogeneity Effect size
I2 (%) p SMD 95% Cl Z p
MCI RT 0 0.492 −0.442 [−0.639, −0.245] 4.39 0.000
Score 50.6 0.009 0.331 [0.146, 0.516] 3.51 0.000
AD Score 62.9 0.000 0.23 [0.065, 0.394] 2.74 0.000

MCI, mild cognitive impairment; AD, Alzheimer’s disease; RT, reaction time; SMD, standardized mean difference; CI, confidence interval.

 Overall effect size

As shown by the overall forest plots (Figures 3A–C), both individuals with MCI and AD benefit from physical activity in terms of VSWM. In studies on MCI, the effect size for research related to scores is SMD = 0.331, p < 0.05. For studies related to reaction time, the effect size is SMD = −0.442, p < 0.05. In AD studies, the effect size is SMD = 0.23, p < 0.05 (Table 3).

Effect of RT and score outcome measures. (A) MCI-Score. (B) MCI-RT. (C) AD.

 Subgroup analysis results of MCI studies

In the score group, when the intervention duration was ≥90 min (SMD = 0.875, p < 0.05), the intervention effect was slightly better than when it was 60–89 min (SMD = 0.242, p < 0.05). The intervention effect for interventions <60 min was not significant. Significant effect sizes were observed when the intervention period was 90–179 days (SMD = 0.226, p < 0.05) and ≥ 180 days (SMD = 0.517, p < 0.05). When the intervention period was ≤90 days, no significant effect was observed on the improvement of VSWM. Only moderately intense exercise (SMD = 0.455, p < 0.05) had a significant intervention effect; exercising three times per week (SMD = 0.591, p < 0.05) had a more significant intervention effect on VSWM than exercising for less than two times per week (SMD = 0.213, p < 0.05). Exercising five times per week did not produce significant results. Table 4 presents the specific values of the subgroup analysis for MCI regarding score studies.

Results of MCI subgroup analysis.

Moderator Subgroup Type SMD 95%CI Z Q df p
Intervention duration <60 min Score −0.038 [−0.334, 0.257] 0.25 1.13 3 0.799
60–89 min Score 0.242 [0.086, 0.398] 3.04 3.95 8 0.002
RT −0.494 [−0.752, −0.236] 3.75 4.36 4 0.000
≥90 min Score 0.875 [0.146, 0.516] 3.26 10.83 3 0.001
RT −0.34 [−0.671, -0.01] 2.02 1.5 2 0.044
Intervention period <90 days Score 0.365 [−0.192, 0.922] 1.29 19.05 4 0.199
RT −0.426 [−1.037, 0.184] 1.37 1.35 1 0.171
90-179 days Score 0.226 [0.026, 0.427] 2.21 4.10 6 0.027
RT −0.362 [−0.609, −0.114] 2.86 3.38 4 0.004
≥180 days Score 0.517 [0.267, 0.767] 4.05 4.63 4 0.000
RT −0.682 [−1.099, −0.266] 3.21 0 0 0.000
Exercise intensity level Low Score 0.081 [−0.289, 0.45] 0.43 0.02 2 0.669
Moderate Score 0.455 [0.207, 0.703] 3.6 24.56 10 0.000
RT −0.450 [−0.705, −0.196] 3.47 6.26 5 0.001
High Score 0.139 [−0.294, 0.571] 0.63 4.44 2 0.53
RT −0.403 [−0.832, 0.025] 1.84 0.12 1 0.065
Intervention times ≤2 sessions/week Score 0.591 [0.165, 1.016] 2.72 24.96 7 0.006
RT −0.426 [−1.037, 0.184] 1.37 1.35 1 0.171
3–4 sessions/week Score 0.213 [0.042, 0.384] 2.44 2.15 6 0.015
RT −0.362 [−0.609, −0.114] 2.86 0 0 0.004
≥5 sessions/week Score 0.191 [−0.099, 0.482] 1.29 0.04 1 0.197
RT −0.682 [−1.099, −0.266] 3.21 1.35 4 0.001

RT, reaction time; SMD, standardized mean difference; CI, confidence interval. The bold values are statistically significant.

In the reaction time group, an intervention duration of ≥90 min (SMD = −0.340, p < 0.05) had the most significant intervention effect, followed by 60–89 min (SMD = −0.494, p < 0.05). Significant effect sizes were observed when the intervention period was ≥180 days (SMD = −0.682, p < 0.05) and 90–179 days (SMD = −0.362, p < 0.05). No significant improvement in VSWM was observed when the intervention period was ≤90 days. Only moderately intense exercise (SMD = −0.450, p < 0.05) had a significant intervention effect. The effect of exercising five times per week (SMD = −0.682, p < 0.05) was the most significant, followed by three to five times per week (SMD = −0.362, p < 0.05), while exercising less than two times per week was not significant. Table 5 depicts the specific values of the subgroup analysis for reaction time in individuals with MCI.

Results of AD subgroup analysis.

Moderator Subgroup SMD 95% CI Z Q df p
Intervention duration <60 min 0.148 [−0.063, 0.358] 1.38 2.2 4 0.169
60–89 min 0.079 [−0.034, 0.191] 1.38 4.23 9 0.169
≥90 min 0.85 [0.008, 1.693] 1.98 14.76 2 0.048
Intervention period <90 days 0.191 [0.041, 0.340] 2.5 3.87 9 0.012
90–179 days 0.552 [−0.188, 1.291] 1.46 35.07 3 0.144
≥180 days 0.042 [−0.111, 0.194] 0.54 0.62 3 0.592
Exercise intensity level Low 0.065 [−0.138, 0.268] 0.63 0.88 2 0.529
Moderate 0.31 [0.067, 0.554] 2.5 38.31 11 0.013
High 0.167 [−0.188, 0.521] 0.92 4.21 2 0.356
Intervention sessions 1 session/week 0.095 [−0.056, 0.245] 1.23 0.9 4 0.219
2 sessions/week 0.293 [0.01, 0.576] 2.03 43.05 10 0.042
3 sessions/week 0.245 [−0.082, 0.572] 1.47 0.19 1 0.141

SMD, standardized mean difference; CI, confidence interval. The bold values are statistically significant.

 Subgroup analysis results of AD studies

First, the effect of the intervention was found to be significant only when the duration of the intervention was greater than 90 min (SMD = 0.850, p < 0.05). Second, a significant effect size was observed only when the intervention period was ≤90 days (SMD = 0.191, p < 0.05), whereas there was no significant effect on the improvement of VSWM when the intervention period was 90–179 days or ≥ 180 days. Third, Moderate exercise intensity has an ameliorative effect on VSWM of individuals with AD (SMD = 0.31, p < 0.05). Finally, the impact of exercising three times per week (SMD = 0.293, p < 0.05) on the intervention effect regarding VSWM was significant, whereas the impact of the remaining two intervention frequencies on the intervention effect was not. Table 5 displays the specific values of the subgroup analysis for AD.

 Network meta-analysis results of MCI studies

With the exception of the ACUTE intervention, all categories of exercise interventions demonstrated superior outcomes over the non-exercise control group. In the score group, the results of the inconsistency test indicated no inconsistencies among the different types of physical exercise scores (χ2 = 1.67, p = 0.893). The SUCRA ranking shows that MBE ranked the highest, with all five types of physical activity having greater impact rates than the control group; only one type had lower impact rates than the control group. Hence, the SUCRA ranking of the intervention modalities was MBE (82.9), ME (69.8), RE (67.2), AE (57.5), FINGER (42.8), CONTROL (19.0), and ACUTE (10.9), and the differences were statistically significant (p < 0.05). A comparison of the different exercise intervention groups with the control group revealed that all exercise interventions, except for FINGER and ACUTE, had a significant effect on VSWM of individuals with MCI, including MBE (SMD = 0.61, 95% CI: 0.07–1.14), ME (SMD = 0.45, 95% CI: 0.04–0.85), RE (SMD = 0.43, 95% CI: 0.07–0.78), and AE (SMD = 0.34, 95% CI: 0.00–0.68).

In the reaction time group, the results of the inconsistency test demonstrated no inconsistencies among different types of physical exercise scores (χ2 = 1.25, p = 0.264). The SUCRA ranking (Figure 4B) shows that RE (94.5) ranked the highest, followed by ME (58.1), AE (47.2), and finally CONTROL (0.3). The differences were statistically significant (p < 0.05). A comparison of the different exercise intervention groups and the control group revealed that all exercise interventions had a significant effect on VSWM of individuals with MCI, including RE (SMD = -36.91, 95% CI: −64.53 – -9.29), ME (SMD = -12.07, 95% CI: −14.62 – −9.52), and AE (SMD = -14.60, 95% CI: −22.94 – –6.25). The network plots are presented in Figures 4A,B. All exercise intervention groups displayed in the comparative form were directly compared with the non-exercise control group (Figures 5A,B). Table 6 presents the SUCRA results.

Network meta-analysis of the comparison for different types of exercise interventions. (A) MCI-Score. (B) MCI-RT. (C) AD. Each node represents one intervention, and the connecting lines between the two nodes represent one or more RCTS in which the two interventions are directly compared. The size of each node is proportional to the number of participants randomly assigned, and the thickness of the lines connecting the two nodes is weighted according to the number of RCTS among the interventions that directly compare their connections.

Results of the SUCRA. (A) MCI-Score. (B) MCI-RT. (C) AD. AE, aerobic exercise; ACUTE, acute exercise; CON, control group; FINGER, finger exercises; MBE, mind–body exercises; ME, multicomponent exercise; RE, resistance exercise.

Results of the SUCRA.

Treatment SUCRA PrBest MeanRank
A (MCI-Score)
MBE 82.9 49.6 2.0
ME 69.8 19.3 2.8
RE 67.2 14.8 3.0
AE 57.5 3.5 3.6
FINGER 42.8 12.1 4.4
CON 19.0 0.0 5.9
ACUTE 10.9 0.7 6.3
B (MCI-RT)
RE 94.5 88.5 1.2
ME 58.1 9.0 2.3
AE 47.2 2.5 2.6
CON 0.3 0.0 4.0
C (AD)
AE 84.1 59.9 1.5
RE 74.0 35.4 1.8
ME 30.7 4.8 3.1
CON 11.2 0.0 3.7

The MeanRank indicates the ranking with the highest probability for the corresponding technique, and SUCRA shows the probability of the technique that rank highest for each outcome; SUCRA, surface under the cumulative ranking curve; MCI, mild cognitive impairment; AD, Alzheimer’s disease; MBE, mind–body exercises; ME, multicomponent exercises; RE, resistance exercises; AE, aerobic exercises; FINGER, finger exercises; CON, control group; ACUTE, acute exercises.

 Network meta-analysis results of AD studies

All types of exercise interventions produced superior outcomes to the non-exercise control group. The results of the inconsistency test showed no inconsistencies between the scores of the different types of physical activity (χ2 = 3.40, p = 0. 182). The SUCRA ranking indicated that AE ranked best compared to the control group, with all three exercise interventions having higher impact effects than the control group; AE (84.1), RE (74.0), and ME (30.7) were higher than the CONTROL (11.2), and the differences were statistically significant (p < 0.05). The network plot is shown in Figure 4C. A comparison of the different exercise intervention groups with the control group demonstrated that all exercise interventions, except for ME, had a significant effect on the VSWM of individuals with MCI, including AE (SMD = 0.39, 95% CI: 0.06–0.71) and RE (SMD = 0.32, 95% CI: 0.02–0.61). The network plot is depicted in Figure 4C. All exercise intervention groups presented in the comparative form were directly compared with the non-exercise control group (Figure 5C).

 Discussion Summary of the evidence

This network meta-analysis explored how exercise therapies affected MCI and AD patients’ VSWM. Previous research only included traditional meta-analyzes comparing exercise regimens on healthy individuals’ VSWM, omitting ME.No publication bias was seen in MCI or AD research. In scores-based studies of MCI patients, MBE had the best results, followed by ME and RE. In reaction time experiments, ME, RE, and MBE were the most effective interventions. AD trials showed AE was most effective, followed by RE (Figure 6).

Comparative effectiveness results for MCI-Score (A), MCI-RT (B), and AD (C). Each cell showed a 95%CI SMD. Important results are shown in bold. CI, confidence interval; AE, aerobic exercise; MBE, mind–body exercise; ME, multicomponent exercise; RE, resistance exercise; SMD, standardized mean difference.

MBE, ME, RE, and AE were each found to enhance the VSWM of individuals with MCI. MBE incorporates a combination of physical exercise and various forms of cognitive training, such as social interaction or mental function exercises. AE is a component of MBE, and there is a connection between sustained AE and increased volume in both the left and right hippocampi of older adults (70). This suggests a correlation between AE and VSWM (71). The hippocampus is a brain region that is strongly associated with learning and memory; a larger hippocampal volume implies a greater number of neurons and synaptic connections that can effectively process and integrate VSWM information (72). Interventions that involve MBE and ME may have a stronger impact on the VSWM of individuals with MCI compared to singular forms such as AE and RE. This aligns with the viewpoint that an enriched cognitive environment may safeguard cognitive function in individuals with MCI (73). In an environment rich in multisensory feedback, this rich sensory stimulation facilitates greater neuronal signal transmission and synaptic plasticity (74).

Viewing reaction time as an outcome measure, MBE, RE, and ME improved the speed of individuals with MCI performing VSWM tasks. The impact of RE on the VSWM of individuals with MCI aligns with previous research showing that RE can strengthen connectivity in the networks of the temporal–parietal junction in the right hemisphere, the ventrolateral prefrontal cortex, and the dorsolateral prefrontal cortex, all of which are associated with response speed during cognitive tasks, in individuals with MCI (75). The improvement in the speed of VSWM tasks through ME and MBE in the MCI group is consistent with the results of a previous intervention study that focused on the working memory of women with MCI (76). Both ME and MBE emphasize integration between different components, mobilizing cognitive resources, and maintaining a focus on body awareness and action planning during the intervention process, ultimately leading to improved speed in VSWM tasks for individuals with MCI (77). Long-term engagement in MBE and ME provides a wide range of cognitive stimuli that contribute to the accumulation of greater cognitive reserve in individuals with MCI. These findings align with the cognitive reserve hypothesis (78).

AD research has mostly used scores to assess the effects of exercise therapy on VSWM tasks. I2 = 62.9% showed moderate heterogeneity in AD studies with no publication bias. Inconsistency tests revealed no substantial inconsistencies. Both AE and RE had significant intervention effects on the VSWM of individuals with AD, demonstrating the efficacy of AE and RE across different stages of cognitive impairment. However, ME did not improve the VSWM of individuals with AD, which is consistent with prior meta-analytic results (79). This could be attributed to the fact that ME interventions typically involve two or more types of exercises and multiple exercise tasks, potentially limiting the physical and cognitive abilities of individuals with AD and making it more challenging to achieve the optimal effects of a single-mode exercise intervention.

The impact of AE on the VSWM of individuals with AD can be explained as follows: AE can enhance neuronal activity and maintain normal functioning of the hippocampus. In addition, AE has the potential to reduce the rate of hippocampal atrophy in individuals with AD (80). The improvement in VSWM of individuals with AD achieved through RE may be associated with fat-free mass (FFM) of the limbs. A cross-sectional study involving 70 patients with AD who underwent magnetic resonance imaging scans found that the FFM of their limbs was positively correlated with their whole-brain volume (81). Additionally, in a study comparing FFM among individuals, those with lower FFM had a 1.43-fold higher probability of developing cognitive impairment than those with higher FFM (82). These findings suggest that strengthening FFM through RE can positively affect cognitive function. Our study also supports the feasibility of RE; however, further RCTs are required to elucidate the specific mechanisms underlying AD.

While APOE-4 was not specifically examined as a subgroup in our meta-analysis, it is important to highlight that there is a correlation between APOE and the efficacy of exercise intervention. APOE-4 is a significant genetic risk for Alzheimer’s disease (83). A research of 70-year-olds showed that individuals without APOE-4 benefit from physical activity in terms of protection against the disease, whereas those with APOE-4 do not (84). In a different cohort study with an average age of 50 years, carriers of the APOE-4 allele exhibited more robust protective effects from exercise compared to non-carriers (85). Neural damage accumulating in individuals with the APOE ε4 gene variant may be too severe to benefit from the therapeutic effects of physical exercise. Despite the presence of the APOE ε4 gene, individuals should still be encouraged to engage in physical activity due to its significant physical health advantages.

This subgroup analysis will help discover heterogeneity and allow for tailored exercise recommendations by comparing effect sizes across subgroups. A selective effect of single-mode intervention time, duration, intensity, and weekly frequency was found. Subgroup analysis of single-session intervention time in MCI trials showed no statistically significant effect size for interventions under 60 min. A significant impact size was usually detected when the intervention lasted beyond 60 min. The effect magnitude was greatest when the intervention lasted over 90 min (SMD = 0.875, 95% CI: 0.349–1.407). The study indicates that moderate exercise intensity significantly enhances VSWM in patients with MCI and AD. A recent study found that moderate to high-intensity exercise has similar beneficial effects on cognitive function in patients with cognitive impairment (86). A small number of high-intensity intervention experiments were used in our study, and all of the subjects were over 70 years old. This may be why the effect size of high-intensity exercise was not statistically significant. In AD research, an effective response is only evident when the intervention duration reaches 90 min or longer. Conversely, previous meta-analytic studies on the VSWM of healthy individuals have found that interventions lasting less than 60 min were effective (87). Our findings thus raise an intriguing question: Does greater cognitive impairment necessitate longer interventions to yield significant effects? This question warrants further investigation.

In addition to providing scientifically based exercise intervention programs, the willingness of cognitively impaired patients to participate is also crucial. Research has shown that exercise support from caregivers and social interaction with peers of similar cognitive levels can increase the exercise participation willingness of cognitively impaired patients (88). Additionally, the community environment can influence the exercise willingness of cognitively impaired patients. For instance, whether the community offers cognitively disabled patients exercise facilities, equipment, and specialist instruction and assistance.

Future research should expand this focus by investigating the VSWM of individuals with MCI across different age groups and by conducting long-term intervention studies on AD. These studies should involve continuous follow-up and provide detailed intervention protocols, including single-session intervention duration as well as intervention components, duration, and intensity. Comparing the differences between specific exercise programs is also highly necessary. Exploring the effects of more exercise programs on individuals with MCI and AD can help provide more effective and diverse exercise regimes. This study performed direct comparisons between the various intervention components. Although we gathered data from four direct comparisons, the number of intervention components was limited. Current research on VSWM is also fairly limited, with most studies failing to separately analyze data related to VSWM, instead incorporating working memory assessments. This approach is potentially problematic as it may yield inaccurate outcomes.

 Limitations

This study has five limitations. Owing to the limited direct comparisons between different exercise interventions, our results are subject to increased uncertainty, and caution is warranted in interpreting the findings. Second, ME interventions do not have a standardized composition, with variations in the duration and intensity of each component. Hence, different ME regimens may have different effects. Future research may benefit from defining the specific components of multi-modal exercises and exploring the effect sizes associated with different multi-modal exercise approaches. Third, a wide variety of tools are available for assessing VSWM, with different measurement instruments exhibiting varying levels of reliability and validity. Due to the lack of race and gender comparisons in the previous literature, we did not conduct an analysis. However, there are certain racial disparities in cognitive impairment, and it is worth noting that there were more female participants in our sample. Therefore, discussing gender and race as variables is essential. These differences may lead to variations in effect sizes, necessitating careful consideration when selecting and interpreting the pooled effect sizes. Finally, this review primarily focused on older adults. As such, our conclusions are mostly applicable to older adults with MCI and AD. Future studies should include participants from different age groups to identify more comprehensive intervention strategies.

 Conclusion

Our meta-analysis supports the notion that long-term physical exercise has a moderately beneficial effect on VSWM in individuals with MCI and AD, and it identifies optimal exercise intervention strategies applicable to these populations. Integrating the results of subgroup and network meta-analyzes, we recommend the following exercise regimens:

For individuals with MCI: Engage in moderate-intensity exercise(VO2max 50–75%) three to four times per week; interventions should exceed 60 min in duration and extend over a period of at least 3 months or longer; exercise modalities include MBE (e.g., Tai Chi, yoga), ME, RE (e.g., resistance band exercises, half squats, heel raises), and AE (e.g., indoor/outdoor walking, treadmill exercise, cycling training, stepping exercises). When opting for ME, we recommend incorporating aerobic exercise, resistance training, and balance training, while considering the individual’s physical condition. For individuals with AD: Engage in moderate-intensity exercise twice a week (VO2max 50–75%); interventions should exceed 90 min in duration and extend over a period of at least 3 months or longer; exercise modalities include AE and RE (same as mentioned in MCI). We also recommend that individuals with MCI and AD participate in exercise groups to enhance social interaction and increase motivation for exercise participation, thereby fostering adherence to long-term exercise.

Healthcare professionals selecting exercise programs should consider factors such as cost-effectiveness, safety, and the physical and social accessibility of required exercise facilities. Additionally, an assessment of individual physical condition and consideration of weather-related factors should be conducted in advance. In conclusion, our meta-analysis underscores the positive impact of exercise interventions on VSWM in individuals with MCI and AD.

 Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

 Author contributions

JD: Data curation, Formal analysis, Investigation, Visualization, Writing – original draft. HW: Supervision, Writing – review & editing. TF: Methodology, Writing – original draft. CX: Formal analysis, Writing – original draft. QZ: Investigation, Writing – review & editing. LG: Writing – review & editing. YZ: Conceptualization, Methodology, Supervision, Writing – review & editing.

 Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Fundamental Research Funds for the Central Universities (Project Title: SWU2309501 and SWU2309720), the Graduate Student Research and Innovation Program of Southwest University (Project Title: SWU23040), and the National Social Science Fund Western Project (Project Title: 23XSH005).

We would like to thank all authors for their encouragement and guidance throughout this project.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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 References Baddeley A Hitch G. Working memory. Psychol Learn Motiv. (1974) 8:47. doi: 10.1016/S0079-7421(08)60452-1 Baddeley AD Andrade J. Working memory and the vividness of imagery. J Exp Psychol Gen. (2000) 129:126. doi: 10.1037/0096-3445.129.1.126, PMID: 10756490 Logie RH. Spatial and visual working memory: mental workspace In: Ross BH, editor. Psychology of learning and motivation. Cambridge, MA: Academic Press (2003). 37–78. Baddeley AD Logie RH. Working memory: The multiple-component model. Cambridge: Cambridge University Press (1999). Baddeley A. Working memory: an overview In: Pickering SJ, editor. Working memory and education. Amsterdam: Elsevier (2006). 1–31. Ausén B. “I Don’t recognize myself”: Personality characteristics in subjective cognitive impairment and mild cognitive impairment. Sweden: Karolinska Institute (2013). Mitchell AJ Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia–meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand. (2009) 119:252–65. doi: 10.1111/j.1600-0447.2008.01326.x Gu L Chen J Gao L Shu H Wang Z Liu D . Deficits in visual-spatial working memory and executive function in single versus multiple-domain amnestic mild cognitive impairment: a combined ERP and sLORETA study. Clin Neurophysiol. (2019) 130:739. doi: 10.1016/j.clinph.2019.01.025, PMID: 30903827 Lou W Shi L Wang D Tam CWC Chu WCW Mok VCT . Decreased activity with increased background network efficiency in the amnestic MCI during a visual-spatial working memory task. Hum Brain Mapp. (2015) 36:3387–403. doi: 10.1002/hbm.22851, PMID: 26032982 Zou Z Liu C Che C Huang H. Clinical genetics of Alzheimer’s disease. Biomed Res Int. (2014) 2014:291862. doi: 10.1155/2014/291862, PMID: 24955352 Kosslyn SM Alpert NM Thompson WL Chabris CF Rauch SL Anderson AK. Identifying objects from different viewpoints: a PET investigation. Brain. (1994) 5:1055–71. doi: 10.1093/brain/117.5.1055 Villemagne VL Pike KE Chételat G Ellis KA Mulligan RS Bourgeat P . Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann Neurol. (2011) 69:181–92. doi: 10.1002/ana.22248, PMID: 21280088 Robertshawe P. Effect of physical activity on cognitive function for Alzheimer's disease. J Aust Trad-Med Soc. (2008) 14:161–2. Nokia MS Lensu S Ahtiainen JP Johansson PP Koch LG Britton SL . Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained. J Physiol. (2016) 594:1855–73. doi: 10.1113/JP271552, PMID: 26844666 Sleiman SF Henry J Al-Haddad R El Hayek L Abou Haidar E Stringer T . Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife. (2016) 5:e15092. doi: 10.7554/eLife.15092, PMID: 27253067 Sehn LFB Schuch FB Firth J Stigger FDS. Effects of physical exercise on cognitive function of older adults with mild cognitive impairment: a systematic review and meta-analysis. Arch Gerontol Geriatr. (2020) 89:104048. doi: 10.1016/j.archger.2020.104048 Chang YK Huang CJ Chen KF Hung TM. Physical activity and working memory in healthy older adults: an ERP study. Psychophysiology. (2013) 50:1174–82. doi: 10.1111/psyp.12089, PMID: 31605625 Lachman ME Neupert SD Bertrand R Jette AM. Effects of strength training on memory in older adults. J Aging Phys Act. (2006) 14:59–73. doi: 10.1123/japa.14.1.59, PMID: 16648652 Parial LL Kor PPK Sumile EF Leung AYM. Dual-task zumba gold for improving the cognition of people with mild cognitive impairment: a pilot randomized controlled trial. Gerontologist. (2022) 63:1248–61. doi: 10.1093/geront/gnac081 Öhman H Savikko N Strandberg TE Pitkälä KH. Effects of physical exercise on cognitive performance in older adults with mild cognitive impairment or dementia: a systematic review. Dement Geriatr Cogn Disord. (2014) 38:347–65. doi: 10.1159/000365388, PMID: 25171577 Gates N Singh MAF Sachdev PS Valenzuela M. 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) 21:1086–97. doi: 10.1016/j.jagp.2013.02.018, PMID: 29588062 Zhang K Zhang Q Jiang H Du J Zhou C Yu S . Impact of aerobic exercise on cognitive impairment and oxidative stress markers in methamphetamine-dependent patients. Psychiatry Res. (2018) 266:328–33. doi: 10.1016/j.psychres.2018.03.032, PMID: 29588062 Eckardt N Braun C Kibele A. Instability resistance training improves working memory, processing speed and response inhibition in healthy older adults: a double-blinded randomised controlled trial. Sci Rep-UK. (2020) 10:2506. doi: 10.1038/s41598-020-59105-0 Suzuki T Shimada H Makizako H Doi T Yoshida D Ito K . A randomized controlled trial of multicomponent exercise in older adults with mild cognitive impairment. PLoS One. (2013) 8:e61483. doi: 10.1371/journal.pone.0061483, PMID: 23585901 Luo SS Chen L Wang GB Wang YG Su XY. Effects of long-term Wuqinxi exercise on working memory in older adults with mild cognitive impairment. Eur Geriatr Med. (2022) 13:1327–33. doi: 10.1007/s41999-022-00709-2, PMID: 36327046 Diederich K Bastl A Wersching H Teuber A Strecker JK Schmidt A . Effects of different exercise strategies and intensities on memory performance and neurogenesis. Front Behav Neurosci. (2017) 11:47. doi: 10.3389/fnbeh.2017.00047, PMID: 28360847 Zou L Yu Q Liu S Loprinzi PD. Exercise on visuo-spatial memory: direct effects and underlying mechanisms. Am J Health Behav. (2020) 44:169–79. doi: 10.5993/AJHB.44.2.5, PMID: 32019650 Morawietz C Muehlbauer T. Effects of physical exercise interventions on spatial orientation in children and adolescents: a systematic scoping review. Front Sports Act Living. (2021) 3:156. doi: 10.3389/fspor.2021.664640 Law M Alam N Veroniki AA Yu Y Jackson D. Two new approaches for the visualisation of models for network meta-analysis. BMC Med Res Methodol. (2019) 19:1–18. doi: 10.1186/s12874-019-0689-9 Hutton B Salanti G Caldwell DM Chaimani A Schmid CH Cameron C . The prisma extension statement for reporting of systematic reviews incorporating network meta-analyzes of health care interventions: checklist and explanations. Ann Intern Med. (2015) 162:777–84. doi: 10.7326/M14-2385, PMID: 26030634 Maher CG Sherrington C Herbert RD. Reliability of the PEDro scale for rating quality of randomized controlled trials. Phys Ther. (2003) 83:713–21. doi: 10.1093/ptj/83.8.713, PMID: 12882612 Colcombe S Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. (2003) 14:125–30. doi: 10.1111/1467-9280.t01-1-01430, PMID: 12661673 Cisternas NS. ACSM guidelines for exercise testing and prescription. Indianapolis, IN: ACSM (2019). MacInnis MJ Gibala MJ. Physiological adaptations to interval training and the role of exercise intensity. J Physiol. (2017) 595:2915–30. doi: 10.1113/JP273196, PMID: 27748956 Borer KT. Exercise endocrinology. Champaign, IL: Human Kinetics (2003). Sinaei M Alaei H Nazem F Kargarfard M Feizi A Talebi A . Endurance exercise improves avoidance learning and spatial memory, through changes in GABA and relaxin-3 genes in rats. Biochem Biophys Res Commun. (2021) 566:204–10. doi: 10.1016/j.bbrc.2021.05.080, PMID: 34214757 Yoon DH Jun-Young L Wook S. Effects of resistance exercise training on cognitive function and physical performance in cognitive frailty: a randomized controlled trial. J Nutr Health Aging. (2018) 22:944–51. doi: 10.1007/s12603-018-1090-9, PMID: 30272098 Gavelin HM Eskilsson T Boraxbekk CJ Josefsson M Neely AS Järvholm LS. Rehabilitation for improved cognition in patients with stress-related exhaustion disorder: RECO – randomized clinical trial. Stress. (2018) 21:279–91. doi: 10.1080/10253890.2018.1461833, PMID: 29693483 Li PW Yu DS Siu PM Wong SC Chan BS. Peer-supported exercise intervention for persons with mild cognitive impairment: a waitlist randomized controlled trial (the BRAin vitality enhancement trial). Age Aging. (2022) 51:afac213. doi: 10.1093/ageing/afac213 Eskilsson T Järvholm LS Gavelin HM Neely AS Boraxbekk CJ. Aerobic training for improved memory in patients with stress-related exhaustion: a randomized controlled trial. BMC Psychiatry. (2017) 17:322. doi: 10.1186/s12888-017-1457-1 Dannhauser TM Cleverley M Whitfield TJ Fletcher BC Stevens T Walker Z. Complex multimodal activity intervention to reduce the risk of dementia in patients with mild cognitive impairment: a pilot and feasibility study for a randomized controlled trial. BMC Psychiatry. (2014) 14:129. doi: 10.1186/1471-244X-14-129 Devenney KE Guinan EM Kelly ÁM Mota BC Walsh C Rikkert MO . Acute high-intensity aerobic exercise affects brain-derived neurotrophic factors in mild cognitive impairment: a randomized controlled study. BMJ Open Sport Exerc Med. (2019) 5:e000499. doi: 10.1136/bmjsem-2018-000499, PMID: 31258928 Hong SG Kim JH Jun TW. Effects of a 12-week resistance exercise program on electroencephalogram patterns and cognitive function in elderly individuals with mild cognitive impairment: a randomized controlled trial. Clin J Sport Med. (2018) 28:500–8. doi: 10.1097/JSM.0000000000000476, PMID: 28727639 Scherder EJ Van Paasschen J Deijen JB Van Der Knokke S Orlebeke JFK Burgers I . Physical activity and executive function in elderly individuals with mild cognitive impairment. Aging Ment Health. (2005) 9:272–80. doi: 10.1080/13607860500089930 Nagamatsu LS Chan A Davis JC Beattie BL Graf P Voss MW . Physical activity improves verbal and spatial memory in older adults with probable mild cognitive impairment: a 6-month randomized controlled trial. J Aging Res. (2013) 2013:861893. doi: 10.1155/2013/861893, PMID: 23509628 Jeong MK Park KW Ryu JK Kim GM Jung HH Park H. Multi-component intervention program on habitual physical activity parameters and cognitive function in patients with mild cognitive impairment: a randomized controlled trial. Int J Environ Res Public Health. (2021) 18:6240. doi: 10.3390/ijerph18126240, PMID: 34207701 Avenali M Picascia M Tassorelli C Sinforiani E Bernini S. Evaluation of the efficacy of physical therapy on cognitive decline at 6-month follow-up in Parkinson disease patients with mild cognitive impairment: a randomized controlled trial. Aging Clin Exp Res. (2021) 33:3275–84. doi: 10.1007/s40520-021-01865-4, PMID: 33978924 Suzuki T Shimada H Makizako H Doi T Yoshida D Tsutsumimoto K . Effects of multicomponent exercise on cognitive function in older adults with mild amnestic cognitive impairment: a randomized controlled trial. BMC Neurol. (2012) 12:1–9. doi: 10.1186/1471-2377-12-128, PMID: 23113898 Yang Y Xingping H Wang W Zhiping L. Clinical application of aerobic exercise combined with resistance exercise in elderly patients with non-dementia cognitive impairment after stroke. Geriatr Health. (2018) 24:265–8. Wang Q Sheng Y. The effect of tai chi exercise on cognitive function of elderly people with mild cognitive impairment in the community. Chinese J Rehabil Theory Prac. (2016) 22:5. doi: 10.3969/j.issn.1006-9771.2016.06.005 Lam LCW Chan WC Kwok TCY Lee JSW Yu BML Lee S . Combined physical exercise-working memory training on slowing down cognitive decline in elders with mild clinical Alzheimer disease: a randomised controlled study (abridged secondary publication). Hong Kong Med J. (2022) 3:28–30. van de Rest O van der Zwaluw NL Tieland M Adam JJ Hiddink GJ Van Loon LJ . Effect of resistance-type exercise training with or without protein supplementation on cognitive functioning in frail and pre-frail elderly: secondary analysis of a randomized, double-blind, placebo-controlled trial. Mech Ageing Dev. (2014) 136:85–93. doi: 10.1016/j.mad.2013.12.005 Makino T Umegaki H Ando M Cheng XW Ishida K Akima H . Effects of aerobic, resistance, or combined exercise training in older adults with subjective memory complaints: a randomized controlled trial. J Alzheimers Dis. (2021) 82:701–17. doi: 10.3233/JAD-210047, PMID: 38456068 Barnes DE Santos-Modesitt W Poelke G Kramer AF Castro C Middleton LE . The mental activity and eXercise (MAX) trial: a randomized controlled trial to enhance cognitive function in older adults. JAMA Intern Med. (2013) 173:797–804. doi: 10.1001/jamainternmed.2013.189, PMID: 23545598 Hoffmann K Sobol NA Frederiksen KS Beyer N Vogel A Vestergaard K. Moderate-to-high-intensity physical exercise in patients with Alzheimer’s disease: a randomized controlled trial. J Alzheimers Dis. (2016) 50:443–53. doi: 10.3233/JAD-150817, PMID: 32536853 Bossers WJ van der Woude LH Boersma F Hortobágyi T Scherder EJ van Heuvelen MJ. A 9-week aerobic and strength training program improved cognitive and motor function in patients with dementia: a randomized controlled trial. Am J Geriatr Psychiatry. (2015) 23:1106–16. doi: 10.1016/j.jagp.2014.12.191, PMID: 25648055 Cheng ST Chow PK Song YQ Edwin CS Chan AC Lee TM . Mental and physical activity delay cognitive decline in older adults with dementia. Am J Geriatr Psychiatry. (2014) 22:63–74. doi: 10.1016/j.jagp.2013.01.060, PMID: 23582750 Yu F Vock DM Zhang L Salisbury D Nelson NW Chow LS. Cognitive effects of aerobic exercise in Alzheimer’s disease: a pilot randomized controlled trial. J Alzheimers Dis. (2021) 80:233–44. doi: 10.3233/JAD-201100, PMID: 33523004 Huang N Li WJ Rong X Champ M Wei L Li M . Effects of a modified tai chi program on older adults with mild dementia: a randomized controlled trial. J Alzheimers Dis. (2019) 72:947–56. doi: 10.3233/JAD-190487, PMID: 31743998 Lautenschlager NT Cox KL Flicker L Foster JK Bockxmeer V. Effect of physical activity on cognitive function in older adults at risk of Alzheimer’s disease: a randomized trial. JAMA. (2008) 300:1027–37. doi: 10.1001/jama.300.9.1027, PMID: 18768414 Cavalcante BR de Souza MF Falck RS Liu-Ambrose T Behm DG Pitangui ACR . Effects of resistance exercise with instability on cognitive function (REI study): a proof-of-concept randomized controlled trial in older adults with cognitive complaints. J Alzheimers Dis. (2020) 77:227–39. doi: 10.3233/JAD-200349, PMID: 32804132 Prick AE De Lange J Scherder E Twisk J Pot AM. Effects of a multicomponent dyadic intervention with physical exercise on the cognitive functioning of people with dementia: a randomized controlled trial. J Aging Phys Act. (2017) 25:539–52. doi: 10.1123/japa.2016-0038, PMID: 28120631 Sanders LMJ Hortobágyi T Karssemeijer EGA Van der Zee EA Scherder EJA Van Heuvelen MJG. Effects of low-and high-intensity physical exercise on physical and cognitive function in older persons with dementia: a randomized controlled trial. Alzheimers Res Ther. (2020) 12:28. doi: 10.1186/s13195-020-00597-3 Pedroso RV Ayán C Fraga FJ da Silva TM Cancela JM Santos-Galduròz RF. Effects of functional task training in older adults with Alzheimer’s disease. J Aging Phys Act. (2018) 26:97–105. doi: 10.1123/japa.2016-0147, PMID: 28513303 Stein AM Coelho FGDM Vital-Silva TM Rueda AV Pereira JR Deslandes AC. Aerobic training and circulating neurotrophins in patients with Alzheimer’s disease: a controlled trial. Exp Aging Res. (2023) 49:1–17. doi: 10.1080/0361073X.2022.2048586, PMID: 35253623 Liao YY Chen IH Hsu WC Tseng HY Wang RY. Effect of exergaming versus combined exercise on cognitive function and brain activation in frail older adults: a randomized controlled trial. Ann Phys Rehabil Med. (2021) 64:101492. doi: 10.1016/j.rehab.2021.101492, PMID: 33454398 Law LL Barnett F Yau MK Gray MA. Effects of functional task exercise on older adults with cognitive impairment at risk of Alzheimer’s disease: a randomized controlled trial. Age Aging. (2014) 43:813–20. doi: 10.1093/ageing/afu055 Thaiyanto J Sittichoke C Phirom K Sungkarat S. Effects of a multicomponent exercise program on cognitive performance and fall risk in older women with mild cognitive impairment. J Nutr Health Aging. (2021) 25:160–4. doi: 10.1007/s12603-020-1458-5, PMID: 33491029 Law LL Mok VC Yau MM. Effects of functional task exercise on cognitive function in older adults with mild cognitive impairment: a randomized controlled pilot trial. Alzheimers Res Ther. (2019) 11:98. doi: 10.1186/s13195-019-0548-2 Voss MW Erickson KI Prakash RS Chaddock L Malkowski E Alves H . Functional connectivity: a source of variance in the association between cardiorespiratory fitness and cognition? Neuropsychologia. (2010) 48:1394–406. doi: 10.1016/j.neuropsychologia.2010.01.005, PMID: 20079755 Erickson KI Prakash RS Voss MW Chaddock L Hu L Morris KS . Aerobic fitness is associated with hippocampal volume in elderly individuals. Hippocampus. (2009) 19:1030–9. doi: 10.1002/hipo.20547, PMID: 19123237 Wirt RA Hyman JM. Integrating spatial working memory and remote memory: interactions between the medial prefrontal cortex and hippocampus. Brain Sci. (2017) 7:43. doi: 10.3390/brainsci7040043 Pang TY Hannan AJ. Enhancement of cognitive function in brain disease models through environmental enrichment and physical activity. Neuropharmacology. (2013) 64:515–28. doi: 10.1016/j.neuropharm.2012.06.029, PMID: 22766390 Rampon C Jiang CH Dong H Tang YP Lockhart DJ Schultz PG. Effects of environmental enrichment on gene expression in the brain. Proc Natl Acad Sci. (2000) 97:12880–4. doi: 10.1073/pnas.97.23.12880, PMID: 11070096 Luks TL Oliveira M Possin KL Bird A Miller BL Weiner MW . Atrophy in these two attention networks is associated with performance on flanker tasks in neurodegenerative diseases. Neuropsychologia. (2010) 48:165–70. doi: 10.1016/j.neuropsychologia.2009.09.001, PMID: 19747928 Kasai JYT Busse AL Magaldi RM Soci MA Rosa PDM Esper Curiati JA . Effects of tai chi chuan on cognition in elderly women with mild cognitive impairment. Einstein (São Paulo, Brazil). (2010) 8:40–5. doi: 10.1590/s1679-45082010ao1470, PMID: 26761751 Zheng G Liu F Li S Huang M Tao J Chen L. Tai chi and the protection of cognitive ability: a systematic review of prospective studies in healthy adults. Am J Prev Med. (2015) 49:89–97. doi: 10.1016/j.amepre.2015.01.002, PMID: 26094229 Yang SY Lee HC Huang CM Chen JJ. Efficacy of tai chi-style multi-component exercise on frontal-related cognition and physical health in elderly with amnestic mild cognitive impairment. Front Aging. (2021) 2:636390. doi: 10.3389/fragi.2021.636390, PMID: 35822039 Anheyer D Klose P Koch AK Haller H Dobos G Cramer H. Comparative efficacy of different exercise interventions in chronic non-specific low back pain: protocol of a systematic review and network meta-analysis. BMJ Open. (2020) 10:e036050. doi: 10.1136/bmjopen-2019-036050, PMID: 32759244 Yang SY Shan CL Qing H Wang W Zhu Y Yin MM . The effects of aerobic exercise on cognitive function of Alzheimer’s disease patients. CNS Neurol Disord Drug Targets. (2015) 14:1292–7. doi: 10.2174/1871527315666151111123319, PMID: 26556080 Burns JM Johnson DK Watts A Swerdlow RH Brooks WM. Reduced lean mass in early Alzheimer disease and its association with brain atrophy. Arch Neurol. (2010) 67:428–33. doi: 10.1001/archneurol.2010.38, PMID: 20385908 Nourhashemi F Andrieu S Gillette-Guyonnet S Reynish E Albarede JL Grandjean H . Is there a relationship between fat-free soft-tissue mass and low cognitive function? Results of the study of 7,105 women. J Am Geriatr Soc. (2002) 2002:1796–801. doi: 10.1046/j.1532-5415.2002.50507.x Rovio S Kåreholt I Helkala EL Viitanen M Winblad B Tuomilehto J . Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol. (2005) 4:705–11. doi: 10.1016/S1474-4422(05)70198-8, PMID: 16239176 Fenesi B Fang H Kovacevic A Oremus M Raina P Heisz JJ. Physical exercise moderates the relationship of apolipoprotein E (APOE) genotype and dementia risk: a population-based study. J Alzheimers Dis. (2017) 56:297–303. doi: 10.3233/JAD-160424, PMID: 27911292 Bierer LM Hof PR Purohit DP Carlin L Schmeidler J Davis KL . Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer's disease. Arch Neurol. (1995) 52:81–8. doi: 10.1001/archneur.1995.00540250089017, PMID: 7826280 Yu DJ Yu AP Bernal JD Fong DY Chan DK Cheng CP . Effects of exercise intensity and frequency on improving cognitive performance in middle-aged and older adults with mild cognitive impairment: a pilot randomized controlled trial on the minimum physical activity recommendation from WHO. Front Physiol. (2022) 13:1021428. doi: 10.3389/fphys.2022.1021428 Zhu Q Deng J Yao M Xu C Liu D Guo L . Effects of physical activity on visual-spatial working memory in healthy individuals: a systematic review and meta-analysis. Front Psychol. (2023) 14:1103003. doi: 10.3389/fpsyg.2023.1103003 Hobson N Dupuis SL Giangregorio LM Middleton LE. Perceived facilitators and barriers to exercise among older adults with mild cognitive impairment and early dementia. J Aging Phys Act. (2019) 28:208–218.89.