Abstract
Abstract
Objectives
Numerous studies have examined the effects of physical activity on cognitive performance and executive function in people with Alzheimer’s disease (AD), although the findings are not entirely consistent. There are also insufficient study reviews for specific workout and assessment tool types. Therefore, the purpose of this study was to systematically investigate the effects of aerobic exercise on the quality of life, cognitive performance and depressive symptoms in people with AD.
Design
Risk of bias was assessed using the Cochrane risk of bias tool, systematic reviews and meta-analyses using random-effects modelling, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation tool.
Data sources
PubMed, Web of Science, Cochrane Library, EMBASE, Scopus, CINAHL and CNKI through 12 March 2024.
Eligibility criteria
The analysis includes all randomised controlled trials (RCTs) that used aerobic exercise as an intervention for individuals with AD.
Data extraction and synthesis
Two writers selected and searched for data using defined techniques. To investigate possible sources of heterogeneity between studies, meta-regression was carried out using Stata MP V.18.0 and V.14.0 software, standardised mean differences (SMDs) and 95% CIs were computed, and data were reviewed using Review Manager V.5.4 software, which was made available by the Cochrane Collaboration. Sensitivity analyses were employed to ascertain the stability and reliability of the results, and funnel plots and Egger’s test were employed to check for publication bias. Correction and assessment of publication bias was done using Duval and Tweedie clipping methods.
Results
Aerobic exercise enhanced cognitive function. For the Minimum Mental State Examination (MMSE) (SMD=0.95, 95% CI 0.58 to 1.32, Z=5.06, p<0.00001), Alzheimer’s Disease Assessment Scale-Cognitive Section (ADAS-cog) (SMD=−0.67, 95% CI −1.15 to –0.2, Z=2.77, p=0.006) and quality of life (SMD=0.36, 95% CI 0.08 to 0.64, Z=2.51, p=0.01), but not statistically significant for depressive symptoms (SMD=−0.25, 95% CI −0.63 to 0.13, Z=1.27, p=0.21). Subgroup analysis showed that duration greater than 16 weeks and less than 50 min per intervention improved MMSE Scores. Duration greater than 16 weeks and more than 30 min per intervention improved ADAS-cog Scores in patients with AD. Aerobic exercise greater than 16 weeks, with more than three interventions per week and 30–50 min per intervention improves quality of life in patients with AD.
Conclusion
The study revealed that aerobic exercise was conducive to the improvement of cognitive function and quality of life among patients with AD, yet it did not exert a significant impact on the amelioration of depressive symptoms. Nevertheless, given the high level of heterogeneity and the variations in the quality of the included studies, the conclusions require further verification through more scientifically objective RCTs.
PROSPERO registration number
CRD42024526067
Keywords: Aged, 80 and over; Exercise; Adult psychiatry
STRENGTHS AND LIMITATIONS OF THIS STUDY.
Inclusion and exclusion criteria were clearly defined to identify all relevant articles concerning the effects of aerobic exercise on individuals with Alzheimer’s disease.
In these trials, blinding of the participants was infeasible, thereby rendering performance bias inevitable throughout all the trials.
About exercise intensity, as some studies failed to provide a description, the subgroups analysed based on intensity were not covered in the article.
The study exhibits a relatively high level of heterogeneity.
Introduction
Approximately 90% of dementia cases among the elderly are attributed to Alzheimer’s disease (AD), which is also one of the most prevalent neurodegenerative diseases within this population.1 AD is an irreversible neurological disorder that undermines social functioning and daily life activities, characterised by cognitive, functional and behavioural deterioration.2 3 A multitude of memory issues, aphasia, disabilities, visual impairments, executive dysfunctions, as well as behavioural and personality disorders are frequently associated with AD.1,4
As life expectancy increases and the population ages, the prevalence of AD is expected to keep rising globally. By 2040, it is predicted to double every 20 years, with the global prevalence reaching up to 24 million cases.5 Especially in developing countries, this will lead to a costly disease burden.3 Currently, an estimated 6.7 million Americans aged 65 years and older are suffering from AD. By 2060, this figure may increase to 13.8 million, and by the middle of the next century, it is expected to reach 14 million.6 According to official death certificates, AD was the sixth most common cause of death in the USA in 2019, with 121 499 documented deaths. AD was the seventh most common cause of death in 2020 and 2021, when COVID-19 ranked among the top 10 causes of mortality.7 The financial burden of this disease is substantial. In 2017, the annual cost of caring for an individual over 65 years old with AD or another form of dementia in the USA was $48 000, which is three and a half times the cost of caring for an individual without dementia. AD is the most common cause of dementia.8 In Poland, there are more than 300 000 people with AD, mainly elderly people.9 In Europe, a meta-analysis estimated that the prevalence and incidence of AD in Europe are 5.05% and 11.08 per 1000 person-years, respectively.10 As average life expectancy continues to increase, AD is projected to become a major socioeconomic burden shortly, potentially affecting 131.5 million people worldwide by 2050.11
Patients with AD may exhibit a variety of abnormal behaviours, including sadness, aggression and apathy, along with a progressive loss of episodic memory, cognitive function, language and visuospatial skills.12 More effective methods are needed to improve the cognitive function and quality of life of patients with AD. Treating AD is a long-term, costly and ineffective process, imposing enormous economic and emotional burdens on the patient’s family and society. However, in terms of pharmacological treatment, there are no specific and reliable drugs for AD13 and evidence established by several studies strongly suggests that the use of some specialty drugs (eg, cholinesterase inhibitors) increases the risk of adverse events in patients with AD.14
Non-pharmacological therapies are designed as a safe, relatively inexpensive and scalable intervention for maintaining cognitive performance in AD.14 A growing body of research indicates that physical activity, one of these approaches, is recognised as a non-pharmacological therapy associated with better cardiovascular and mental health (such as anxiety and depression).15,17 Moreover, more studies are demonstrating that physical activity is positively correlated with cognitive performance in adults.18,20
People with AD can now benefit from a variety of exercise regimens, including combined, resistance and aerobic workouts. Numerous studies have demonstrated the beneficial effects of physical activity on cognitive function. Lautenschlage,21 Kramer,22 Kemoun23 and Yang24 have shown that physical activity and exercise may slow cognitive decline. Heyn et al25 have shown that physical activity and exercise have a positive effect on cognition in patients with cognitive decline. Yágüez et al26 conducted a study showing that short-term non-aerobic exercise was effective in improving some aspects of cognitive functioning in patients with AD. Other studies have observed that physical activity does not have a positive effect on cognitive function in patients with AD.27 Littbrand et al28 found that a systematic evaluation of whether physical activity improves cognitive function in patients with dementia is inconclusive, and most studies have shown that exercise does not affect cognitive function.
Middle-aged and older adults benefit more from aerobic exercise since it is easier, more convenient and offers a greater degree of freedom. The effects of aerobic exercise in middle-aged and older persons have been the subject of an increasing number of studies; however, prior research has mostly examined the effects of many types of exercise in these patients rather than focusing on particular exercise types. For instance, Su Susana Lopez-Ortiz discovered that only aerobic exercise is significant when evaluating the benefits of various forms of exercise (aerobic, strength or combination training) on patients with AD.29 According to Rui-Xia Jia, exercise and physical activity can help older persons with AD think more clearly.30 In her study, Shiyan Zhang primarily examined how aerobic exercise affected cognitive performance in patients with AD using the Minimum Mental State Examination (MMSE) Score Scale. She discovered a substantial impact on the rise in MMSE Scale Scores.31
In this study, our focus was on screening seven databases and separately analysing the measurement tools of aerobic exercise regarding cognitive function (MMSE and Alzheimer’s Disease Assessment Scale-Cognitive Section (ADAS-cog)) in terms of outcome indicators, aiming to enhance the effect on the quality of life and depression of patients with AD. Consequently, we carried out a comprehensive systematic evaluation and meta-analysis of randomised controlled trials (RCTs) to explore whether aerobic exercise is beneficial to the improvement of cognitive function, quality of life and depression in patients with AD.
Methods
Reporting and registration protocol
The systematic evaluation has been registered in the International Prospective Registry of Systematic Evaluation (PROSPERO, registration number: CRD42024526067). This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines32 (online supplemental file 1).
Databases and search strategy
A systematic literature search was performed for eligible studies published before 12 March 2024, across seven databases, namely PubMed, Cochrane Library, Excerpta Medica Database (Embase), Web Of Science, Scopus, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and CNKI (China National Knowledge Infrastructure). All the articles retrieved from each database were screened for duplicates and organised with the aid of EndNote (V.X9) reference management software. In addition to investigating the effects of aerobic exercise on cognitive function and quality of life in patients with AD, reference tracking of published trials and meta-analysis reviews within the field was also conducted. The principal strategy adopted in this paper is the Medical Subject Headings (MESH) term search strategy, which combines MESH subject terms and free words for term searching. Article screening was mainly carried out by two authors (LY and ZY). In case of discrepancies, CP would negotiate and make a judgement. For more details regarding the search strategy, please refer to the online supplemental file 2. All analyses were based on published studies; hence, neither ethical approval nor patient consent was required.
Eligibility criteria
The inclusion criteria are as follows:
Population: Patients with AD. This search is not confined to any specific population or age group to ensure a comprehensive meta-analysis.
Intervention: The sample should involve aerobic exercise.
Control group: There should be a control group with different interventions, such as routine care, stretching and stretching exercises.
Results: The main outcome measures should comprise data regarding the cognitive function, quality of life or depression of patients with AD.
Study design: Only RCT studies conducted in both English and Chinese were included.
Exclusion criteria
The exclusion criteria were as follows:
The exclusion criteria encompassed comments, letters, editorial comments, case reports, conference abstracts and unpublished articles.
Studies lacking the quantification of results or corresponding outcome measures were excluded.
Articles inaccessible through various channels and methods were excluded.
Documents with inferior quality were excluded.
Studies that combined aerobic and anaerobic exercises and those that combined aerobic and cognitive exercises were excluded.
Data extraction
The titles and abstracts of the studies identified during the initial search were imported into EndNote for initial screening. After eliminating duplicates and reviews, and excluding animal experiments, the titles, abstracts, and full texts were further retrieved and analysed. The data were independently extracted by two authors. Any disagreement will be resolved either by consulting a third author or through discussion until a consensus is reached. From each study, we collected the following data: authors, year of publication, country, sample size, intervention, gender, age, type of intervention, frequency of intervention, duration of intervention, intensity of intervention, and outcome indicators. Some of the studies were from the same article, but because their effect estimates were the most independent (eg, samples from different groups, intervention modalities, etc), we believe that they can be considered independent effects for meta-analyses and that this approach has been validated in similar studies.
Risk of bias
Risk of bias was assessed using the Cochrane Collaboration tool for assessing risk of bias 2 (RoB2; V.2) to assess potential bias in the inclusion of RCTs.33 Five domains of bias were synthesised: the randomisation process, departures from the intended intervention, missing outcome data, outcome measures and selection of reported outcomes. A study could be assessed as ‘low risk of bias’ if all domains were assessed as ‘low risk’; if at least one domain was assessed as ‘some concern’, the study could be assessed as ‘some concern’; if at least one domain was assessed as ‘high risk’ or at least three domains were assessed as ‘some concern’, the study could be assessed as ‘high risk of bias’. The risk of bias was assessed independently by two researchers (LY and ZY). Disagreements were resolved by consensus or by involving a third researcher (CP).
Grading the quality of evidence
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to assess the quality of the evidence provided by the meta-analyses for the different outcomes.34 Each outcome could be rated as high, moderate, low or very low evidence based on study design, RoB, inconsistency, circumstantial evidence, imprecision and publication bias.
Data analysis
Meta-analysis was performed using the Cochrane Collaboration’s Review Manager V.5.4 software, and statistical significance was defined as a value of p<0.05 (all reported values of p were two-sided). Significance was defined as a value of p<0.05 (all reported values of p were two-sided). The outcome of this study was a continuous variable, and we calculated the standardised mean difference (SMD) and 95% CI. Judging the heterogeneity between the studies, where a value of p<0.05 was used as the significance level, and the heterogeneity was assessed using the I² statistic, I² (0–25%), I² (25%), I² (50%) and I² (75%) indicate no heterogeneity, mild heterogeneity, moderate heterogeneity and high heterogeneity, respectively. When I² ≥50%, a random-effects model is used, and when I² <50%, a fixed-effects model is used. In case of high heterogeneity (I2≥50%), subgroup analysis or sensitivity analysis was used to interpret the results. To investigate possible sources of heterogeneity between studies, meta-regression was carried out using Stata MP V.18.0 and V.14.0 software, SMDs and 95% CIs were computed, and data were reviewed using Review Manager V.5.4 software, which was made available by the Cochrane Collaboration. Sensitivity analyses were employed to ascertain the stability and reliability of the results, and funnel plots and Egger’s test were employed to check for publication bias. Publication bias was corrected and assessed using the Duval and Tweedie clipping methods.
Subgroup analysis
In subgroup analyses, we endeavoured to explore the effects on cognitive functioning and quality of life by using country (China and other countries), number of weeks (16 weeks or less, and more than 16 weeks), duration of a single intervention (less than 30 min, 30–50 min, and 50 min or more) and frequency of weekly interventions (less than three times per week or three times per week and more). The analysis was conducted using RevMan V.5.4 software. In terms of the overall effect, a value of p<0.05 was considered statistically significant.
Patient and public involvement
None.
Results
Search outcomes
From the establishment of the database until March 2024, we conducted a literature search. The initial search yielded 3877 citations (519 from the PubMed database, 5422 from the Embase database, 899 from Scopus, 777 from the Cochrane library, 896 from Web of Science, 16 from CINAHL and 348 from CNKI). Using EndNote, we removed duplicates. Through reviewing titles, abstracts and full texts, a total of 21 trials were included in the final research review using the inclusion and exclusion criteria (online supplemental file 3).
Characteristics of the studies
The descriptive characteristics of the 21 included studies are shown in online supplemental file 3. A total of 1286 subjects were included in the studies, of which 681 (53%) were female and 605 (47%) were male. The age range of subjects was 60–90 years, most of which were concentrated between 70 years and 85 years. The literature included was mainly from seven different countries. One study was from Brazil,35 1 from Saudi Arabia,36 2 from France,23 37 1 from Denmark,38 4 from USA,39,42 2 from Italy,43 44 1o from China.2445,53
Among the intervention outcome indicators, 17 studies were related to cognitive function, 10 studies were related to quality of life and 3 studies were related to depression in patients with AD. Cognitive function was assessed by MMSE and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAD-cog), quality of life was assessed by Short Form 36 Health Survey (SF-36), Quality of Life in Alzheimer's Disease (QoL-AD), EQ5D and Disability Assessment for Dementia (DAD), and depression was assessed by Beck Depression Inventory (BDI), 17-item Hamilton Depression Rating Scale (HAMD-17) and Cornell Scale for Depression. The duration of a single exercise intervention was 30–90 min, the intervention period was 8–64 weeks, and the frequency of the intervention was two to five times per week. For more details on the intervention characteristics and outcome measures, see online supplemental file 4.
Risk of bias assessment
According to the RoB2 assessment, 19 studies found some problems and 2 studies showed an overall bias of low RoB. In terms of the randomisation process, it was assessed as inconclusive mainly because the studies did not clearly describe the randomisation process. In terms of interventions that deviated from expectations, the nature of the studies did not allow for blinding of subjects and intervention providers. In terms of missing outcome data, most of the studies had less than 10% missing respondents, except Wangwei2014, a study with a high number of missing respondents. In terms of outcome measures, all studies collected data in the form of scales, which is more objective. In terms of the choice of reported outcomes, most studies did not develop or could not inquire about previous research plans and were assessed as inconclusive (online supplemental file 5).
Quality of evidence
According to the GRADE results summary, the main limitations were study design, risk of bias, imprecision, inconsistency, indirectness and effect size among the included RCTs. Thus, the quality of the MMSE and ADAS-cog studies was very low, whereas that of the quality of life studies was moderate (online supplemental file 5).
Meta-analysis
Cognitive ability: MMSE
Fourteen articles were incorporated into the MMSE Scale analysis concerning cognitive functioning in individuals with AD. Among these, three articles were classified into two types of aerobic intervention intensity, thereby bringing the total number of studies to 17.
The combined effect of the intervention group on the MMSE Scales was statistically significant compared with the control group (SMD=0.95, 95% CI 0.58 to 1.32, Z=5.06, p<0.00001), but the studies showed a high degree of heterogeneity (p<0.00001 for the test of heterogeneity, I2=83%), and to account for heterogeneity between the 17 studies, we performed a further subgroup analysis (figure 1).
Figure 1. MMSE Scale of the effects of aerobic exercise on cognitive function. MMSE, Minimum Mental State Examination.
Cognitive ability: ADAS-cog
Seven articles were incorporated into the ADAS-cog Scale analysis related to cognitive functioning in individuals with AD. Among these, two articles were classified into two types of aerobic intervention intensity, thus bringing the total number of studies to nine.
The combined effect was statistically significant in the intervention group compared with the control group (SMD=−0.67, 95% CI −1.15 to –0.2, Z=2.77, p=0.006), but the studies showed a high degree of heterogeneity (p<0.0001 for the test of heterogeneity, I2=84%), and further subgroup analyses were carried out to account for heterogeneity among the nine studies (figure 2).
Figure 2. ADAS-cog Scale of the effects of aerobic exercise on cognitive function. ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognitive Section.
Quality of life
Eight articles were incorporated into the analysis related to the quality of life of individuals with AD. Among them, one article involved two types of aerobic intervention intensity, thereby bringing the total number of studies to nine.
The combined effect was statistically significant in the intervention group compared with the control group (SMD=0.36, 95% CI 0.08 to 0.64, Z=2.51, p=0.01), but the studies showed moderate heterogeneity (p=0.003 for heterogeneity test, I2=65%), and further subgroup analyses were performed to account for heterogeneity among the nine studies (figure 3).
Figure 3. The effect of aerobic exercise on the quality of life.
Depression
Three articles were included in the analysis regarding depression in patients with AD. The combined effect was not statistically significant in the intervention group compared with the control group (SMD=−0.25, 95% CI −0.63 to 0.13, Z=1.27, p=0.21) (figure 4).
Figure 4. The effects of aerobic exercise on depressive symptoms.
Sensitivity analysis
Sensitivity analyses were conducted using a case-by-case exclusion method, with the vertical line labelled ‘estimate’ indicating the pooled results of all included studies and the lines on either side indicating the CIs for those results. Circles corresponding to any particular study indicate the pooled results of the remaining studies after excluding that particular study. If the circle remains close to the ‘estimate’ line and within the original CI after excluding a study, this indicates that the exclusion of this study does not significantly change the combined results. This consistency implies that the results are robust.
In the MMSE sensitivity analysis, after excluding the Hoffmann (2016) Study, the circles were outside the CIs, and after excluding this article (SMD=1.02, 95% CI 0.65 to 1.39, Z=5.4, p<0.00001), there was no significant change in the overall effect estimate and CIs of the meta-analysis, indicating that the combined effect was robust and the results do not change significantly due to outliers in individual studies (online supplemental file 6).
The findings for the two outcome measures (ie, ADAS-cog and quality of life) indicate that the point estimates of the composite effect sizes obtained with the exclusion of specific studies are within the 95% CI of the overall composite effect size. This suggests that excluding specific studies does not significantly alter the results, indicating stability in the assessment of the two outcome measures (online supplemental file 6).
Publication bias
Seventeen studies investigated the MMSE indicators of cognitive performance in patients with AD. To evaluate publication bias, possible publication bias was visually detected by examining funnel plots (see online supplemental file 6). Egger’s linear regression test was employed, and table 1 presents the results of the analysis of MMSE (t=3.72, 95% CI 1.96 to 7.24, p=0.002), which implies that publication bias might influence the observed outcomes. Consequently, we used the Duval and Tweedie trimming method to assess publication bias. After five iterations of the analysis, the software estimated the number of missing studies to be four (online supplemental file 6). After adjusting for potential publication bias, the effect of the intervention remained statistically significant, suggesting no significant alteration in outcomes and stable results.
Table 1. Egger’s linear regression test.
| Outcomes | Egger | Duval and Tweedie clipping | |
| T | P value | P value | |
| MMSE | 3.72 | 0.002 | 0.011 |
| ADAS-cog | −2.78 | 0.027 | 0.006 |
| Quality of life | 0.65 | 0.534 | |
ADAS-cogAlzheimer’s Disease Assessment Scale-Cognitive SectionMMSEMinimum Mental State Examination
Nine studies investigated the ADAS-cog indicators of cognitive performance in patients with AD. To evaluate publication bias, possible publication bias was visually detected by examining funnel plots (online supplemental file 6). Egger’s linear regression test was employed, and table 1 presents the results of the ADAS-cog analysis (t=−2.78, 95% CI −12.89 to −1.03, p=0.027), which implies that publication bias might affect the observed results. Consequently, we used the Duval and Tweedie trimming method to assess publication bias. After two iterations of the analysis, the software estimated the number of missing studies to be 0 (online supplemental file 6). This indicates that there is no significant evidence of missing studies in the available data. It implies that the included studies are likely to be sufficiently comprehensive within the available literature of the study, being free of substantial publication bias and having stable results.
Nine studies investigated the indicators of quality of life in patients with AD. To evaluate publication bias, Egger’s linear regression test was employed by examining the funnel plot visualisation to determine the absence of publication bias (online supplemental file 6). The results demonstrated that there was no significant difference between the two conditions (p>0.05), and Egger’s linear regression analysis indicated the absence of publication bias.
Subgroup analysis
Cognitive ability: MMSE Scale
To further investigate the impacts of aerobic exercise on the cognitive performance of patients with AD as well as the sources of heterogeneity, subgroup analyses were carried out based on country, intervention period, intervention frequency and intervention duration. By MMSE Scale division, in terms of country, studies in China (SMD=0.93, 95% CI 0.49 to 1.37) and other countries (SMD=0.95, 95% CI 0.58 to 1.32) have shown the ability to improve cognitive function in people with AD. Studies with a duration of more than 16 weeks (SMD = 1.68, 95% CI 0.78, 2.58) show greater improvement in cognitive function in Alzheimer's disease (AD) patients compared to those with a duration of 16 weeks or less (SMD = 0.68, 95% CI 0.32, 1.04). Smaller differences in effects between groups were observed with varying weekly frequencies of interventions. A duration of ≤30 minutes per intervention (SMD = 1.44, 95% CI 0.99, 1.88) improves cognitive function in Alzheimer's disease (AD) patients more than interventions lasting ≤50 minutes and >30 minutes (SMD = 0.91, 95% CI 0.31, 1.51), and more than interventions lasting >50 minutes (SMD = 0.76, 95% CI −0.17, 1.68), (online supplemental file 7).
Cognitive ability: ADAS-cog Scale
For the ADAS-cog Scale of cognitive function in patients with AD, in terms of country classification, studies in China (SMD=−0.60, 95% CI −1.03 to –0.16) showed improved cognitive performance, whereas studies in other countries (SMD=−0.02, 95% CI −0.34 to 0.30) showed no statistical significance. In terms of duration, ＞16 weeks (SMD=−1.02, 95% CI −1.86 to –0.19) improved cognitive performance, while ≤16 weeks (SMD=−0.30, 95% CI −0.61 to 0.01) showed no statistical significance. In terms of single intervention duration, studies of 30 min (SMD=−1.02, 95% CI −1.86 to –0.19) were more effective than those of ≤30 min (SMD=−0.30, 95% CI −0.61 to 0.01), (online supplemental file 7).
Quality of life
For quality of life in patients with AD, in terms of country division, studies in China (SMD=0.53, 95% CI 0.21 to 0.86) showed significantly improved quality of life, while studies in other countries (SMD=0.15, 95% CI −0.24 to 0.53) showed no statistical significance. In terms of duration, >16 weeks (SMD=0.69, 95% CI 0.43 to 0.96) showed significantly improved quality of life, while ≤16 weeks (SMD=0.18, 95% CI −0.15 to 0.5) was not statistically significant. In terms of intervention frequency, >3 times per week (SMD=0.68, 95% CI 0.36 to 0.99) significantly improved quality of life, while ≤3 times per week (SMD=0.26, 95% CI −0.06 to 0.58) was not statistically significant. Duration of each intervention ≤50 > 30 minutes (SMD=0.44, 95%CI CI 0.04-0.83) improved quality of life in AD patients. However, there was no statistically significant difference between ≤30 minutes (SMD=0.27, 95%CI CI -0.39, -0.93) and >50 minutes (SMD=0.33, 95%CI CI - -0.39, -1.06), (online supplemental file 7).
Discussion
This systematic evaluation accompanied by meta-analysis delved into the impacts of aerobic exercise on cognitive function, quality of life and depression among patients with AD. In contrast to prior meta-analyses, specific types of exercise were highlighted, particular scales were used, and the effects on quality of life were examined. Out of an initial search yielding 3877 articles, 21 randomised controlled studies were ultimately selected for this study. The findings demonstrated that aerobic exercise exerted a significant influence on the enhancement of MMSE and ADAS-cog Scores, as well as on the improvement of quality of life in patients with AD, while there was no statistically significant difference in the relief of depressive symptoms.
Numerous studies have demonstrated that exercise is beneficial for cognitive functioning.54,56 Specifically, aerobic exercise has been proven to improve or stabilise overall cognition in older adults.57,59 First, animal studies have shown that exercise can promote neuroplasticity60 61 and induce an increase in hippocampal neurogenesis. Moreover, aerobic fitness has been found to enhance blood flow, glucose utilisation and oxygen extraction, thereby improving the brain’s functional and structural reserves.62 63 In animal models, aerobic exercise has been demonstrated to favourably modify the accumulation, degradation and removal of the hallmark amyloid-β and hyperphosphorylated τ proteins of AD. Additionally, aerobic exercise seems to impact non-marker pathologies of AD, such as neuroinflammation, oxidative stress and glucose metabolism hypoplasia.54 Exercise promotes the secretion of brain-derived neurotrophic factor, which is associated with learning and memory.64,66 Exercise reduces certain chronic diseases (eg, cardiovascular disease, obesity, diabetes, etc) as well as risk factors associated with dementia and other cognitive dysfunctions.67 Tyndall et al68 have proposed that physical activity, particularly aerobic exercise, exerts a positive influence on blood biomarkers, and physiological and psychological factors associated with cognitive function through multiple mechanisms.
Physical activity serves as an important means to enhance muscle strength, muscle mass and balance, and reduce ADL dependence, thereby improving the quality of life of individuals.36 69 70 When analysing the changes in quality of life in response to aerobic exercise training among patients with AD, several studies have indicated that exercise interventions may improve health-related quality of life and mental health36 71 72 such as aerobic and resistance exercise helps to improve the ability to perform activities of daily living in people with dementia.73 A recent study found that patients with dementia had improved Activities of Daily Living (ADL) performance and quality of life following long-term physical activity.74 The studies mentioned above have demonstrated the positive impacts of aerobic exercise on cognitive function and quality of life, which aligns with our findings.
About the cognitive function of patients with AD, the MMSE Scores of the intervention groups involved in the study exhibited a statistically significant difference (p<0.00001), and the ADAS-cog Scale also demonstrated a statistically significant difference (p<0.00001), indicating that aerobic exercise can significantly enhance the cognitive function of patients with AD. Concerning the quality of life of patients with AD, the scores of the intervention groups included in the study presented a statistically significant difference (p=0.003), suggesting that aerobic exercise is positively correlated with the improvement of the quality of life of patients with AD. Regarding the depressive symptoms of patients with AD, the scores of the intervention groups incorporated in the study showed no statistical difference (p=0.1), thereby revealing that no significant effect was detected for aerobic exercise on the depressive mood of patients with AD.
Aerobic exercise significantly increased MMSE, ADAS-cog and Quality of Life Scores in patients with AD in the included studies, but there was some heterogeneity, so subgroup analyses were performed by grouping the studies according to country, weekly frequency of interventions, length of each intervention and total length of interventions. For cognitive function in patients with AD, the MMSE Scale found 83% heterogeneity, and subgroup analysis found that grouping by country, duration, frequency and session time were all statistically significant, but with high heterogeneity. For cognitive function in AD patients, the ADAS-cog Scale found 84% heterogeneity, and in the subgroup analysis, the related studies were in China. The ADAS-cog Scale was found to be statistically significant in the subgroup analysis, >16 weeks in duration and ≥30 min in a single intervention, but there was a high degree of heterogeneity. The heterogeneity for the Quality of Life scale was found to be 56%. In studies conducted in China, interventions lasting more than 16 weeks, with a frequency of more than 3 times per week and a single session duration of 30–50 minutes, were statistically significant, though moderate heterogeneity was observed. Rui-xia Jia, concluded that patients with AD should engage in up to 30 min of physical activity three times per week.30 Barnard et al75 stated that brisk walking for 40 min three times a week as a regular activity can improve cognitive function. In our study, for the MMSE Scores included in the study, a duration of more than 16 weeks and less than 50 min per intervention improved the MMSE Scores and significantly improved cognitive function in patients with AD. For ADAS-cog Scale Scores, greater than 16 weeks and a duration of more than 30 min per intervention improved ADAS-cog Scores in patients with AD. For quality of life, >16 weeks and more than three weekly interventions of 30–50 min each improved quality of life in patients with AD.
However, several limitations were present in this study. It was not possible to blind the participants to the trials in the article, thus making performance bias unavoidable in all the trials. In the subgroup analyses, an insufficient number of studies within each subgroup could also give rise to certain biases in the results. About depressive symptoms, owing to the limited number of eligible RCTs, we were unable to ascertain whether there existed a statistically significant difference between aerobic exercise and depressive symptoms among patients with AD. Concerning exercise intensity, since some studies did not describe it, the subgroups analysed for intensity were not covered in the article. There was a high degree of heterogeneity in this paper on account of differences in study design, sample characteristics and intervention approaches.
In our meta-analysis involving multiple subgroups of cognitive function and quality of life, the majority of subgroups exhibited high heterogeneity during the analysis, particularly in the assessment of cognitive function. Although most subgroups demonstrated statistically significant effects, the high heterogeneity implies substantial differences in the intervention effects among different studies. The heterogeneity might be associated with variations in study design, the diversity of intervention delivery methods, and the heterogeneity of study samples. Specifically, differences in intervention duration, frequency and the type of intervention (such as yoga as opposed to traditional exercise) across studies could be the key factors contributing to the high heterogeneity. Future studies should endeavour to standardise measurement tools and intervention criteria to minimise the interstudy variability, thus enhancing the robustness and credibility of the results.
Conclusion
This systematic evaluation and meta-analysis indicate that aerobic exercise is conducive to improving the cognitive function and quality of life of patients with AD. Interventions lasting more than 16 weeks and less than 50 min have been shown to enhance the MMSE Scores of patients with AD, while interventions that last more than 16 weeks and are longer than 30 min per session can improve the ADAS-cog Scores of patients with AD. Moreover, aerobic exercise regimens that extend over more than 16 weeks, occur more than three times per week and last for 30–50 min per session can enhance the quality of life of patients with AD.
supplementary material
Footnotes
Funding: Hunan Provincial Philosophy and Social Science Fund Project: Research on Folk Sports Helping Social Adaptation of Relocated Residents in the Context of Rural Revitalization (number:22YBA100).
Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-090623).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: Not applicable.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
References
- 1.Yesavage JA, Brooks JO, 3rd, Taylor J, et al. Development of aphasia, apraxia, and agnosia and decline in Alzheimer’s disease. Am J Psychiatry. 1993;150:742–7. doi: 10.1176/ajp.150.5.742. [DOI] [PubMed] [Google Scholar]
- 2.Alzheimer’s Association 2010 Alzheimer’s disease facts and figures. Alzheimers Dement. 2010;6:158–94. doi: 10.1016/j.jalz.2010.01.009. [DOI] [PubMed] [Google Scholar]
- 3.Zhang X-X, Tian Y, Wang Z-T, et al. The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention. J Prev Alzheimers Dis. 2021;8:313–21. doi: 10.14283/jpad.2021.15. [DOI] [PubMed] [Google Scholar]
- 4.Zhang S, Zhang M, Cai F, et al. Biological function of Presenilin and its role in AD pathogenesis. Transl Neurodegener. 2013;2:15. doi: 10.1186/2047-9158-2-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol. 2011;7:137–52. doi: 10.1038/nrneurol.2011.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Forsyth E, Ritzline PD. An Overview of the Etiology, Diagnosis, and Treatment of Alzheimer Disease. Phys Ther. 1998;78:1325–31. doi: 10.1093/ptj/78.12.1325. [DOI] [PubMed] [Google Scholar]
- 7.2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023;19:1598–695. doi: 10.1002/alz.13016. [DOI] [PubMed] [Google Scholar]
- 8.Hebert LE, Weuve J, Scherr PA, et al. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology (ECronicon) 2013;80:1778–83. doi: 10.1212/WNL.0b013e31828726f5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Wales NS, Else-Mitchell R, Haviland S. Report. Citeseer. 1994.
- 10.Niu H, Álvarez-Álvarez I, Guillén-Grima F, et al. Prevalence and incidence of Alzheimer’s disease in Europe: A meta-analysis. Neurol (Engl Ed) 2017;32:523–32. doi: 10.1016/j.nrleng.2016.02.009. [DOI] [PubMed] [Google Scholar]
- 11.Khan A, Corbett A, Ballard C. Emerging treatments for Alzheimer’s disease for non-amyloid and non-tau targets. Expert Rev Neurother. 2017;17:683–95. doi: 10.1080/14737175.2017.1326818. [DOI] [PubMed] [Google Scholar]
- 12.Bateman RJ, Xiong C, Benzinger TLS, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367:795–804. doi: 10.1056/NEJMoa1202753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Zhou S, Chen S, Liu X, et al. Physical Activity Improves Cognition and Activities of Daily Living in Adults with Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Environ Res Public Health. 2022;19:1216. doi: 10.3390/ijerph19031216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Liang J-H, Xu Y, Lin L, et al. Comparison of multiple interventions for older adults with Alzheimer disease or mild cognitive impairment: A PRISMA-compliant network meta-analysis. Medicine (Baltimore) 2018;97:e10744. doi: 10.1097/MD.0000000000010744. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Gordon BR, McDowell CP, Lyons M, et al. The Effects of Resistance Exercise Training on Anxiety: A Meta-Analysis and Meta-Regression Analysis of Randomized Controlled Trials. Sports Med. 2017;47:2521–32. doi: 10.1007/s40279-017-0769-0. [DOI] [PubMed] [Google Scholar]
- 16.Awick EA, Ehlers DK, Aguiñaga S, et al. Effects of a randomized exercise trial on physical activity, psychological distress and quality of life in older adults. Gen Hosp Psychiatry. 2017;49:44–50. doi: 10.1016/j.genhosppsych.2017.06.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Sousa N, Mendes R, Abrantes C, et al. Effectiveness of combined exercise training to improve functional fitness in older adults: A randomized controlled trial. Geriatr Gerontol Int. 2014;14:892–8. doi: 10.1111/ggi.12188. [DOI] [PubMed] [Google Scholar]
- 18.Falck RS, Davis JC, Best JR, et al. Impact of exercise training on physical and cognitive function among older adults: a systematic review and meta-analysis. Neurobiol Aging. 2019;79:119–30. doi: 10.1016/j.neurobiolaging.2019.03.007. [DOI] [PubMed] [Google Scholar]
- 19.Zhu X, Yin S, Lang M, et al. The more the better? A meta-analysis on effects of combined cognitive and physical intervention on cognition in healthy older adults. Ageing Res Rev. 2016;31:67–79. doi: 10.1016/j.arr.2016.07.003. [DOI] [PubMed] [Google Scholar]
- 20.Håkansson K, Ledreux A, Daffner K, et al. BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function. J Alzheimers Dis . 2017;55:645–57. doi: 10.3233/JAD-160593. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Lautenschlager NT, Cox KL, Flicker L, et al. Effect of Physical Activity on Cognitive Function in Older Adults at Risk for Alzheimer Disease. JAMA. 2008;300:1027. doi: 10.1001/jama.300.9.1027. [DOI] [PubMed] [Google Scholar]
- 22.Kramer AF, Erickson KI, Colcombe SJ. Exercise, cognition, and the aging brain. J Appl Physiol. 2006;101:1237–42. doi: 10.1152/japplphysiol.00500.2006. [DOI] [PubMed] [Google Scholar]
- 23.Kemoun G, Thibaud M, Roumagne N, et al. Effects of a Physical Training Programme on Cognitive Function and Walking Efficiency in Elderly Persons with Dementia. Dement Geriatr Cogn Disord. 2010;29:109–14. doi: 10.1159/000272435. [DOI] [PubMed] [Google Scholar]
- 24.Yang S-Y, Shan C-L, Qing H, et al. 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. [DOI] [PubMed] [Google Scholar]
- 25.Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: A meta-analysis11No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Arch Phys Med Rehabil. 2004;85:1694–704. doi: 10.1016/j.apmr.2004.03.019. [DOI] [PubMed] [Google Scholar]
- 26.Yágüez L, Shaw KN, Morris R, et al. The effects on cognitive functions of a movement-based intervention in patients with Alzheimer’s type dementia: a pilot study. Int J Geriatr Psychiatry. 2011;26:173–81. doi: 10.1002/gps.2510. [DOI] [PubMed] [Google Scholar]
- 27.Forbes D, Forbes SC, Blake CM, et al. Exercise programs for people with dementia. Cochrane Database Syst Rev. 2015;2015:Cd006489. doi: 10.1002/14651858.CD006489.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Littbrand H, Stenvall M, Rosendahl E. Applicability and Effects of Physical Exercise on Physical and Cognitive Functions and Activities of Daily Living Among People With Dementia. Am J Phys Med Rehabil. 2011;90:495–518. doi: 10.1097/PHM.0b013e318214de26. [DOI] [PubMed] [Google Scholar]
- 29.López-Ortiz S, Valenzuela PL, Seisdedos MM, et al. Exercise interventions in Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials. Ageing Res Rev. 2021;72:S1568-1637(21)00226-9. doi: 10.1016/j.arr.2021.101479. [DOI] [PubMed] [Google Scholar]
- 30.Jia R, Liang J, Xu Y, et al. Effects of physical activity and exercise on the cognitive function of patients with Alzheimer disease: a meta-analysis. BMC Geriatr. 2019;19:181. doi: 10.1186/s12877-019-1175-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Zhang S, Zhen K, Su Q, et al. The Effect of Aerobic Exercise on Cognitive Function in People with Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Environ Res Public Health. 2022;19:15700. doi: 10.3390/ijerph192315700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi: 10.1136/bmj.l4898. [DOI] [PubMed] [Google Scholar]
- 34.Guyatt GH, Oxman AD, Schünemann HJ. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol J Clin Epidemiol. 2011;64:380–2. doi: 10.1016/j.jclinepi.2010.09.011. [DOI] [PubMed] [Google Scholar]
- 35.Arcoverde C, Deslandes A, Moraes H, et al. Treadmill training as an augmentation treatment for Alzheimer?s disease: a pilot randomized controlled study. Arq Neuro-Psiquiatr. 2014;72:190–6. doi: 10.1590/0004-282X20130231. [DOI] [PubMed] [Google Scholar]
- 36.Abd El-Kader SM, Al-Jiffri OH. Aerobic exercise improves quality of life, psychological well-being and systemic inflammation in subjects with Alzheimer’s disease. Afr Health Sci. 2016;16:1045–55. doi: 10.4314/ahs.v16i4.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Enette L, Vogel T, Merle S, et al. Effect of 9 weeks continuous vs. interval aerobic training on plasma BDNF levels, aerobic fitness, cognitive capacity and quality of life among seniors with mild to moderate Alzheimer’s disease: a randomized controlled trial. Eur Rev Aging Phys Act. 2020;17:2. doi: 10.1186/s11556-019-0234-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Hoffmann K, Sobol NA, Frederiksen KS, et al. Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer’s Disease: A Randomized Controlled Trial. JAD . 2016;50:443–53. doi: 10.3233/JAD-150817. [DOI] [PubMed] [Google Scholar]
- 39.Morris JK, Vidoni ED, Johnson DK, et al. Aerobic exercise for Alzheimer’s disease: A randomized controlled pilot trial. PLoS One. 2017;12:e0170547. doi: 10.1371/journal.pone.0170547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Vidoni ED, Morris JK, Watts A, et al. Effect of aerobic exercise on amyloid accumulation in preclinical Alzheimer’s: A 1-year randomized controlled trial. PLoS One. 2021;16:e0244893. doi: 10.1371/journal.pone.0244893. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Yu F, Thomas W, Nelson NW, et al. Impact of 6-month aerobic exercise on Alzheimer’s symptoms. J Appl Gerontol. 2015;34:484–500. doi: 10.1177/0733464813512895. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Yu F, Vock DM, Zhang L, et al. 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Venturelli M, Scarsini R, Schena F. Six-month walking program changes cognitive and ADL performance in patients with Alzheimer. Am J Alzheimers Dis Other Demen . 2011;26:381–8. doi: 10.1177/1533317511418956. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Venturelli M, Sollima A, Cè E, et al. Effectiveness of Exercise- and Cognitive-Based Treatments on Salivary Cortisol Levels and Sundowning Syndrome Symptoms in Patients with Alzheimer’s Disease. JAD . 2016;53:1631–40. doi: 10.3233/JAD-160392. [DOI] [PubMed] [Google Scholar]
- 45.Chunhong C, Wei W, Yi Z, et al. A study on the intervention effect of aerobic training on Alzheimer’s disease. Chin J Rehabil Med. 2015;30:1131–4. [Google Scholar]
- 46.Liu Y, Wang T, Zhu Y, et al. Moderate-intensity aerobic exercise improves cognitive function in patients with Alzheimer’s disease. China Rehab. 2017;32:386–9. [Google Scholar]
- 47.Ming Q, Ling Z. Effectiveness of resting-state fMRI-based aerobic training in patients with Alzheimer’s disease. Chin J Clin Med Imaging. 2015;26:761–3. [Google Scholar]
- 48.Wang W, Wang T, Sha LJ, et al. Changes in low-frequency amplitude fMRI and cognitive function before and after aerobic exercise in patients with Alzheimer’s disease. Chin J Rehabil Med. 2019;34:371–7. [Google Scholar]
- 49.Wang W, Zhu Y, Yang SY, et al. Effects of aerobic training on cognitive function and activities of daily living in patients with Alzheimer’s disease. Chin J Rehabil Med. 2014;29:1151–5. [Google Scholar]
- 50.Wang Y. Shen F. Zhu Y, et al. A clinical study of moderate- to high-intensity aerobic exercise intervention for Alzheimer’s disease, China Clinical Neuroscience. 2014;22:504–9. [Google Scholar]
- 51.Yanheng WEI, Haili J, Xingxiao H, et al. Effects of aerobic exercise based on Baduanjin on cognitive function and quality of life in patients with mild-to-moderate Alzheimer’s disease. Evid Based Nurs. 2024;10:335–8. [Google Scholar]
- 52.Wu D, Huang K. Effects of walking on cognitive function and quality of life in patients with Alzheimer’s disease. Chin J Mod Med. 2015;25:94–7. [Google Scholar]
- 53.Lanyun Y, Wei W, Feifei S, et al. A clinical study of aerobic exercise with different training times for mild to moderate Alzheimer’s disease. Chin J Rehabil Med. 2015;30:771–6. [Google Scholar]
- 54.Chapman SB, Aslan S, Spence JS, et al. Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging. Front Aging Neurosci. 2013;5:75. doi: 10.3389/fnagi.2013.00075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Yu F, Kolanowski AM, Strumpf NE, et al. Improving Cognition and Function Through Exercise Intervention in Alzheimer’s Disease. J Nurs Scholarsh. 2006;38:358–65. doi: 10.1111/j.1547-5069.2006.00127.x. [DOI] [PubMed] [Google Scholar]
- 56.Stephen R, Hongisto K, Solomon A, et al. Physical Activity and Alzheimer’s Disease: A Systematic Review. GERONA. 2017:glw251. doi: 10.1093/gerona/glw251. [DOI] [PubMed] [Google Scholar]
- 57.Tarumi T, Rossetti H, Thomas BP, et al. Exercise Training in Amnestic Mild Cognitive Impairment: A One-Year Randomized Controlled Trial. JAD. 2019;71:421–33. doi: 10.3233/JAD-181175. [DOI] [PubMed] [Google Scholar]
- 58.Sampaio A, Marques EA, Mota J, et al. Effects of a multicomponent exercise program in institutionalized elders with Alzheimer’s disease. Dementia (London) 2019;18:417–31. doi: 10.1177/1471301216674558. [DOI] [PubMed] [Google Scholar]
- 59.Song D, Yu DSF. Effects of a moderate-intensity aerobic exercise programme on the cognitive function and quality of life of community-dwelling elderly people with mild cognitive impairment: A randomised controlled trial. Int J Nurs Stud. 2019;93:97–105. doi: 10.1016/j.ijnurstu.2019.02.019. [DOI] [PubMed] [Google Scholar]
- 60.Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957;20:11–21. doi: 10.1136/jnnp.20.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.O’Keefe J, Nadel L, Keightley S, et al. Fornix lesions selectively abolish place learning in the rat. Exp Neurol. 1975;48:152–66. doi: 10.1016/0014-4886(75)90230-7. [DOI] [PubMed] [Google Scholar]
- 62.Sahay A, Scobie KN, Hill AS, et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature New Biol. 2011;472:466–70. doi: 10.1038/nature09817. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Swain RA, Harris AB, Wiener EC, et al. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience. 2003;117:1037–46. doi: 10.1016/S0306-4522(02)00664-4. [DOI] [PubMed] [Google Scholar]
- 64.Cotman C. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25:295–301. doi: 10.1016/S0166-2236(02)02143-4. [DOI] [PubMed] [Google Scholar]
- 65.Belarbi K, Burnouf S, Fernandez-Gomez F-J, et al. Beneficial effects of exercise in a transgenic mouse model of Alzheimer’s disease-like Tau pathology. Neurobiol Dis. 2011;43:486–94. doi: 10.1016/j.nbd.2011.04.022. [DOI] [PubMed] [Google Scholar]
- 66.Adlard PA, Perreau VM, Pop V, et al. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J Neurosci . 2005;25:4217–21. doi: 10.1523/JNEUROSCI.0496-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Kalmijn S, Foley D, White L, et al. Metabolic Cardiovascular Syndrome and Risk of Dementia in Japanese-American Elderly Men. ATVB . 2000;20:2255–60. doi: 10.1161/01.ATV.20.10.2255. [DOI] [PubMed] [Google Scholar]
- 68.Tyndall AV, Clark CM, Anderson TJ, et al. Protective Effects of Exercise on Cognition and Brain Health in Older Adults. Exerc Sport Sci Rev. 2018;46:215–23. doi: 10.1249/JES.0000000000000161. [DOI] [PubMed] [Google Scholar]
- 69.Kwak Y-S, Um S-Y, Son T-G, et al. Effect of Regular Exercise on Senile Dementia Patients. Int J Sports Med. 2008;29:471–4. doi: 10.1055/s-2007-964853. [DOI] [PubMed] [Google Scholar]
- 70.Sobol NA, Hoffmann K, Frederiksen KS, et al. Effect of aerobic exercise on physical performance in patients with Alzheimer’s disease. Alzheimer's & Dementia. 2016;12:1207–15. doi: 10.1016/j.jalz.2016.05.004. [DOI] [PubMed] [Google Scholar]
- 71.Brown DW, Balluz LS, Heath GW, et al. Associations between recommended levels of physical activity and health-related quality of life Findings from the 2001 Behavioral Risk Factor Surveillance System (BRFSS) survey. Prev Med. 2003;37:520–8. doi: 10.1016/S0091-7435(03)00179-8. [DOI] [PubMed] [Google Scholar]
- 72.Painter P, Carlson L, Carey S, et al. Physical functioning and health-related quality-of-life changes with exercise training in hemodialysis patients. Am J Kidney Dis. 2000;35:482–92. doi: 10.1016/S0272-6386(00)70202-2. [DOI] [PubMed] [Google Scholar]
- 73.Lam FM, Huang M-Z, Liao L-R, et al. Physical exercise improves strength, balance, mobility, and endurance in people with cognitive impairment and dementia: a systematic review. J Physiother. 2018;64:4–15. doi: 10.1016/j.jphys.2017.12.001. [DOI] [PubMed] [Google Scholar]
- 74.Ojagbemi A, Akin-Ojagbemi N. Exercise and Quality of Life in Dementia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Appl Gerontol . 2019;38:27–48. doi: 10.1177/0733464817693374. [DOI] [PubMed] [Google Scholar]
- 75.Barnard ND, Bush AI, Ceccarelli A, et al. Dietary and lifestyle guidelines for the prevention of Alzheimer’s disease. Neurobiol Aging. 2014;35:S74–8. doi: 10.1016/j.neurobiolaging.2014.03.033. [DOI] [PubMed] [Google Scholar]