Effect of Physical Exercise on Cognitive Function of Alzheimer's Disease Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trial

This review aims to systematically review the effects of physical exercise on the cognitive performance of patients with Alzheimer's disease (AD) and its mechanisms of action. Databases such as Web of Science, PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched until December 2021. A randomized controlled trial (RCT) to assess the effect of an exercise intervention (compared with no exercise) on patients with AD. The measures included cognitive function [Mini-Mental State Examination (MMSE), Alzheimer's Disease assessment scale-cognitive (ADAS-Cog), Montreal cognitive assessment scale (MoCA) and Executive Function (EF)]. The methodological quality of the included literature was assessed using the Physiotherapy Evidence Database (PEDro) scale. Twenty-two studies (n = 1647, mean age: 77.1 ± 6.3 years) were included in the systematic review, sixteen of which were included in the meta-analysis. A systematic review and meta-analysis revealed that physical exercise positively affects cognitive performance in older patients with AD. However, the positive effects of the intervention should be interpreted with caution considering the differences in methodological quality, type, frequency, and duration of exercise in the included studies. Future studies should consider the design rigor and specification of RCT protocols.


INTRODUCTION
Alzheimer's disease (AD) is a chronic neurodegenerative disease that has no known treatable cure (1). As the disease gradually destroys brain structures (e.g., hippocampus and internal olfactory cortex) (2), it leads to loss of cognitive mental functions, including memory, language, attention, and perception, reduced activities of daily living, and diminished quality of life (3).
The global increase in the prevalence of AD is closely linked to the aging of the population (4). According to the World Alzheimer's Disease Report 2021, more than 55 million people worldwide are living with cognitive impairment, which is expected to reach 78 million by 2030 (5). The direct cost to American society of caring for patients with AD was estimated at $305 billion in 2020 and was expected to exceed $1 trillion by 2050 (6). The high cost of treatment prevents 75% of people with dementia worldwide from being effectively diagnosed and treated (5).
Numerous studies have shown that physical exercise is associated with positive effects on brain health (23)(24)(25). High levels of aerobic exercise have been associated with improved brain volume and factors of cognitive decline (26,27). Some studies have shown that aerobic exercise can boost brain plasticity (28), reduce hippocampal atrophy (29), and even increase the hippocampus (30). Physical exercise appears to affect brain atrophy positively in older adults with AD (31). Cognitive impairment is one of the forms of brain atrophy presentation, which results in difficulty in controlling physical mobility in patients with AD (32). Regular exercise at an appropriate intensity and physically demanding level may stimulate some cognitive functions in older adults with AD (33). Therefore, physical exercise appears to be one of the active strategies to resist brain atrophy in older adults with AD. Several reviews have been published on the effects of physical exercise on the cognitive performance of older adults with AD (19,(34)(35)(36)(37). Some reviews concluded that the intervention was beneficial for global cognitive impairment (19,35). Others concluded that the intervention effect was not beneficial (36); some meta-analyses concluded that physical exercise improved cognition in the AD group with an effect comparable to donepezil (38). By way of example, physical exercise can improve cognition. Previous studies have confirmed that physical activity can improve cognition in AD patients, but the dose-effect relationship between physical activity and AD is not clear. Moreover, systematic reviews are lacking for analyzing the type, intensity, frequency, and duration of physical exercise interventions in patients with AD.
Therefore, the purposes of this review were (1) to systematically review the effects of physical exercise on the cognitive performance of patients with AD; (2) to determine the dose-effect of physical exercise on patients with AD, and (3) to explore the mechanisms underlying the effects of physical exercise on the cognitive performance of patients with AD. To this end, we developed a conceptual model of physical exercise interventions for the cognitive performance of AD patients (Figure 1).

Data Sources and Search Strategies
The study of this systematic review and meta-analysis followed the PRISMA guidelines (39). Three databases, including Web of Science, PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, were searched for literature written in English only. The search terms used include "Alzheimer's" or "Alzheimer's disease" or "AD" or "dementia" and "exercise" or "physical exercise" or "aerobic exercise" or "resistance training" and "cognitive function" or "executive function." The search strategy was determined by three investigators, with two investigators working independently on the search task and the third involved in resolving any search disputes. The search covered the period from creating the database to December 31, 2021.

Study Selection
The criteria for inclusion in the study were (1) design: randomized controlled trial (RCT); (2) sample: at least one group of participants with a diagnosis of Alzheimer's disease type dementia in older adults (mean age 65 years or older), excluding other diagnoses of dementia or MCI; (3) intervention: aerobic, resistance, or stretching type of physical exercise was performed; (4) outcome: at least one executive function or cognitive function was measured. The following studies were excluded from systematic evaluation: (1) non-interventional studies; (2) nonexercise type studies of intervention modalities; (3) theoretical studies, descriptions of treatments, or methodological protocols; (4) review articles; and (5) non-English language articles.

Data Extraction
Two investigators (WL and JL) retrieved and collected data, and potential disagreements were resolved by joint discussion with two other investigators (JC and QL). Data collected from each study included subject characteristics (mean age, number of genders), intervention protocol (exercise type, frequency, duration, intensity), indicators of cognitive outcomes, intervention effects, and pre-and post-intervention outcomes (expressed as mean ± standard deviation). The conversion was performed using the formula SD = SEM • √ n for studies that provided standard error of the mean (SEM) for outcomes. When the outcomes data were expressed as mean and confidence interval (CI), the formula for conversion of CI to SD was SD = upper limit−lower limit 3.92 • √ n (40). If some studies only displayed graphs containing means and standard deviations, the GetData Graph Digitizer was used for digitizing and extracting the data (41). All studies included in the meta-analysis were used for data synthesis, regardless of their methodological quality.

Qualitative Analysis
The methodological quality assessment of each study was conducted independently by two reviewers (JZ and YW) using the Physiotherapy Evidence Database (PEDro) Scale (42). The PEDro scale was developed to assess the quality of a treatment or intervention study design, including assessment of randomization, blinding, attrition, design, and statistics. According to the PEDro scale scoring rules, each item was scored independently, with "yes" being scored as "1" and "no" or "unclear" as "0, " and the maximum score for the ten criteria was 10. The possible risk of bias was determined from the extracted information, with <5/10 being rated as "high" risk and more than 5/10 as "low" risk (43). If the details in the article were unclear, we judged the risk of bias as "unclear" and contacted the corresponding author for more information. If the corresponding author did not provide clarification within ten working days, the item was scored as "0."

Statistical Analysis
Review Manager Software V.5.3 was used for statistical analysis of the combined data. Statistical significance was defined for bilateral p < 0.05. The combined data effects were presented using the mean difference (MD) and the corresponding 95%CI of the continuous effects. If data were available and no significant heterogeneity was detected, a fixed-effects model was used to calculate the combined effect. Otherwise, a random-effects model was applied. Statistical heterogeneity was assessed using the I 2 statistic. However, when heterogeneity between studies was high (I 2 > 75%), overall pooled analysis was considered inappropriate; clinical or methodological heterogeneity was considered a potential cause. Heterogeneity between studies was explored using the χ2 test and Higgins I 2 values (44). Studies with different intervention types were divided into subgroups for analysis based on different factors, given the potential heterogeneity between studies.

Study Selection
A total of 2,862 literature records were initially identified according to the proposed search strategy. Two investigators (WL, JL) screened by abstract and title, and apparently irrelevant records were excluded. A total of forty-eight potential studies were included for further evaluation. Of these, sixteen studies that did not provide physical exercise and ten studies that did not involve cognitive outcomes were excluded. Finally, twentytwo studies were eligible for inclusion in the systematic review, and the data from sixteen studies were extracted for metaanalysis. The detailed literature selection and screening process are described in Figure 2.
The frequency of interventions ranged from 2 to 5 times per week for 30-70 min each. The duration of the interventions ranged from 9 to 52 weeks. Participants had heart rate reserve (HRR) from 40 to 80%, maximum oxygen uptake (VO2max) from 60 to 70%, and maximum heart rate (MHR) from 60 to 80% in the inclusion studies. Furthermore, six studies did not describe the intensity of intervention exercise (13-15, 20, 45, 47). The control group interventions generally utilized low-intensity activities/exercises such as social activities, stretching exercises, or health education.

Quality Assessment
Twenty-two studies included in the systematic review were identified with the PEDro score to assess methodological quality.
Only one study had a PEDro score of 5, and the other twenty-one studies had a PEDro score of ≥6, indicating good quality. Nevertheless, we also found fewer studies on participant and therapist blinding in the PEDro quality assessment. Only three studies blinded participants, and only one study blinded therapists. Details of the raw records are shown in Table 2.
Two studies were performed to assess the effect of physical activity on cognitive function using MoCA (12,51). Both studies showed a positive effect of physical exercise on cognitive function. Nevertheless, the meta-analysis showed no significant improvement in MD scores of cognitive functions (n = 86, MD = 3.53, 95% CI = −2.00 to 9.05, p = 0.21; I 2 = 95%, random-effects model; Figure 5).

DISCUSSION
This review examined the effects of physical activity on the cognitive function of older patients with AD. Although 41% of the studies in the systematic review did not show a positive intervention effect, there was a significant improvement in the cognitive performance of patients in 59% of the studies. In the meta-analysis, the studies using the MMSE (p < 0.0001) and ADAS-Cog (p = 0.04) measures of cognitive performance both showed significant improvements, while the studies using the MoCA (p = 0.21) and EF (p = 0.91) tests did not show significant improvements. Thus, we identified that physical exercise interventions are beneficial for improving cognitive function in AD patients.
Several previous meta-analyses reported a significant positive effect of physical exercise interventions on attenuating a cognitive decline in patients with AD (57)(58)(59). The present study was consistent with using the MMSE test for significant positive effects of exercise on cognitive performance interventions. In this study, the percentage of significant studies was higher when analyzing aerobic exercise separately than mixed exercise. For example, aerobic exercise interventions were significant in 67% of the included studies; mixed exercise was 55%. Notably, the benefits of aerobic exercise on cognitive performance in patients with AD appear to be at least similar to the minimal clinically significant differences (MCID) reported in previous studies (60).
Although the findings of this study meta-analysis support the effect of physical exercise on cognitive improvement in patients with AD, it is difficult to determine whether the cognitive improvement is due to the type of exercise (aerobic, resistance, stretching, or mixed), the amount of exercise, or the intensity of exercise. This review includes three exercise types: aerobic exercise, resistance exercise, stretching exercise, and mixed exercise. Both resistance and stretching exercises separately showed a positive effect of the intervention. However, 45% of the studies in mixed exercise did not show a positive effect of the intervention. Moreover, the least amount of exercise in all studies was 540 min (48), and the most were 7,800 min (54), and neither study found a significant cognitive improvement effect. Therefore, this means that the relationship between the amount of exercise and the effect of exercise is not clear. As for exercise intensity, of the fifteen studies in the included literature that involved moderate exercise intensity, 47% had positive intervention effects, while 53% had insignificant effects ( Table 1). It remains to be verified that moderate exercise intensity is the recommended criterion, as mentioned in previous studies (61,62).
The strength of this systematic review is the methodological design, in which the construction of a conceptual model is methodologically focused on the study of the mechanisms of   physical exercise (63). First, we propose a "conceptual model of physical exercise interventions for the cognitive performance of patients with AD." Second, the present study focused on different types of physical exercise, including the intensity, duration, and categories of exercise. In addition, the meta-analysis included randomized controlled trials to ensure the quality of the study literature. The current study also has some limitations. First, the included studies used different measurement instruments and had methodological compatibility issues, which may affect our interpretation of data integration and findings. Second, heterogeneity exists across intervention characteristics, including type, intensity, frequency, and duration of exercise. The type of included studies varied, such as aerobic exercise, resistance exercise, stretching exercise, or mixed exercise; the duration of each exercise session ranged from 30 to 70 min, and the duration ranged from 9 to 52 weeks. Therefore, the optimal design of intervention studies remains unclear, and further research is necessary. Third, the different levels of quality of the included studies and the methodological heterogeneity may lead to our interpretation of the results. Fourth, based on the current systematic review and meta-analysis of studies, we found few studies reporting analysis of the effects of combined interventions (only two), such as physical exercise with cognitive training interventions and physical exercise with pharmacological interventions. We will focus on the above issues in future studies. Additionally, since it is not possible to blind participants in physical exercise intervention experiments; therefore, such bias in the study design may exist.

CONCLUSION
Physical exercise interventions effectively improve cognitive performance in older patients with AD, which may indicate the potential value of physical exercise in improving cognitive performance and preventing conversion to severe dementia in patients with AD. However, considering the differences in methodological quality, type, frequency, and duration of exercise in the included studies, the positive effects of the intervention should be interpreted with caution. More rigorous designs and standardized RCT protocols will be considered for future studies.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.

AUTHOR CONTRIBUTIONS
WL and JL: data collection. JZ and YW: data analysis, conception, and design. WL, JL, JC, and QJ: research design, writing the manuscript, and revision. All authors contributed to the article and approved the submitted version.