R. Cámara-Calmaestra1, A. Martínez-Amat1, A. Aibar-Almazán1, F. Hita-Contreras1, N. de Miguel Hernando2, A. Achalandabaso-Ochoa1
1. Department of Health Sciences, Faculty of Health Sciences, University of Jaén, Jaén, Spain; 2. Department of Surgery, Ophthalmology, Otolaryngology and Physiotherapy, University of Valladolid, 47002 Valladolid, Spain.
Corresponding Author: Agustín Aibar-Almazán, Department of Health Sciences, University of Jaén, E-23071 Jaén, Spain, tel+34-953-213659, fax +34-953-012141, Email: email@example.com
J Prev Alz Dis 2022;
Published online June 7, 2022, http://dx.doi.org/10.14283/jpad.2022.57
Objective: A systematic review of randomized controlled trials was conducted to determine the effect of physical exercise on physical-functional capacity, cognitive performance, neuropsychiatric symptoms, and quality of life in a population of older people with Alzheimer´s disease.
Data sources: Pubmed, Scopus, PEDro, Web of Science, CINAHL, Cochrane Library, grey literature and a reverse search from inception to April 2021 were searched to identify documents.
Study selection: Publications investigating the effect of any type of physical exercise-based intervention in any of its multiple modalities on physical-functional capacity, cognitive performance, neuropsychiatric symptoms, and quality of life were searched.
Data Extraction: The data were extracted into predesigned data extraction tables. Risk of bias was evaluated through the PEDro scale and its internal validity scale.
Data Synthesis: A total of 8 different randomized controlled trials with a total sample of 562 non-overlap Alzheimer disease patients between 50-90 years and a mean age of 75.2 ± 3.9 years were eligible for analyses. Physical-functional capacity was evaluated in 6 of 8 studies and cognitive performance was evaluated in 5 of 8 studies, all of them showed improvements in these variables when compared with the controls, except for two studies in physical-functional capacity and one study for cognitive performance. In the physical-functional capacity and cognitive performance variables, aerobic physical exercise was used in isolation, or in a multimodal way, combining aerobic, strength and balance exercise, from 2 to 7 weekly sessions with doses between 30 and 90 minutes, and a duration of the program comprised of 9 weeks to 6 months. Neuropsychiatric symptoms and quality of life were evaluated in 2 of 8 studies, which the intervention groups experienced significant improvements when compared with the control groups, except for one study that found similar differences in quality of life between both groups. In the neuropsychiatric symptoms and quality of life variables, only aerobic physical exercise was used, in a more homogeneous way, from 2 to 3 weekly sessions with doses of 30 to 60 minutes, and a total program duration of 9 to 16 weeks.
Conclusions: Despite the scarcity of studies, especially those based on multimodal proposals, and the heterogeneity in the protocols, this systematic review found moderate to limited evidence that aerobic physical exercise on its own or combined in a multimodal program that also includes strength and balance exercise can be a useful tool in the management of patients with Alzheimer’s disease with the aim of maintaining and/or improving physical-functional capacity and cognitive performance. In addition, this review found moderate evidence of the positive impact that aerobic physical exercise could have in reducing neuropsychiatric symptoms and improving quality of life in patients with Alzheimer´s disease. PROSPERO registration number: CRD42021229891.
Key words: Aged, Alzheimer disease, exercise, resistance training, physical fitness; cognition.
Abbreviations: 6MWT: 6-Minute walk test; 30-STS: 30-seconds sit-to-stand; AD: Alzheimer´s disease; ADAS-Cog: Alzheimer disease assessment scale-cognitive; BDNF: brain-derived neurotrophic factor; CDR: Clinical dementia rating; CI: confidence interval; DST: Digit span test; EMT: Episodic memory test; EQ-5D: European Quality of Life-5 Dimensions; FIM: Functional independence measure; FRT: Functional reach test; HAMD-17: Hamilton depression rating scale-17 items; IV: Internal validity; NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer; NPI-12: Neuropsychiatric inventory; PE: Physical exercise; PEDro: Physiotherapy evidence database; PICO: Population, intervention, comparison, and outcomes; PPT: Physical performance test; QoL-AD: Quality of life-Alzheimer´s disease; RCTs: Randomized controlled trials; SDMT: Symbol Digit Modalities Test; SPPB: Short physical performance battery; TUG: Timed up and go test.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects memory and cognitive judgment. It is the leading cause of dementia in late adult life. It is also the main cause of dependency, disability, and mortality, generating costs of more than 600 billion dollars in the US alone (1). Today the disease affects approximately 44 million people, and this number is expected to triple by 2050 as the population ages (2). AD is recognized by the World Health Organization as a global public health priority (2).
The neuropathological features of the disease include intracellular neurofibrillary tangles and plaques consisting of deposition of amyloid proteins (3). The risk of developing AD can be attributed in some case to genetics (4). On the other hand, tobacco, sugary beverages, obesity, diabetes, sedentary lifestyle, hypertension, and cardiovascular diseases are dangerously related to its appearance (5–7).
The most common symptom of AD is the insidious presentation of a decreased ability to remember new information (1). Dependence increases along with an early alteration of motor function. A correct differential diagnosis is of paramount importance, as several other causes other than AD may produce memory loss (8).
Currently no treatment has been defined in order to eliminate the pathology. However, some drugs capable of eliminating amyloid proteins are emerging (9), which is one of the two AD pathological hallmarks. Therefore, palliative measures are applied which include pharmacological and non-pharmacological strategies, cognitive training, music therapy, and physical exercise (PE) (5).
PE is defined as planned, structured, and repetitive movement to improve or maintain one or more components of physical fitness (10). It has some components such as type, dose and duration. Nowadays, evidence about the impact of exercise training is considered for several exercise types:
• Aerobic exercise, refers to exercises in which the body’s large muscles move in a rhythmic manner for sustained periods.
• Strength exercise, is exercise that causes muscles to work or hold against an applied force or weight to develop this ability.
• Flexibility exercise is based to activities designed to preserve or extend range of motion around a joint.
• Balance exercise, refers to a combination of activities designed to increase lower body strength and decrease the probability of falling (10).
PE has shown to provide beneficial effects to a large number of AD-related pathologies and problems, such as cardiovascular risk and blood pressure (11). In addition, it has anti-inflammatory and antioxidant effects, and fewer side effects than drugs (11–14). Thus, many authors recommend its use in the treatment of AD (15–21) given the increasing evidence to support its positive effects on mental health, neurodegenerative diseases, and dementias. However, PE interventions presents a great challenge for people with AD, given that they become more difficult as the severity of cognitive decline increases (22).
Due to the numerous beneficial effects derived from the regular practice of PE, it is capable of combating most of the modifiable risk factors that currently predispose to AD, and there is also evidence that suggests a protective association between PE and suffering from AD (23–25). This, together with the exponential concern for problems related to aging and the benefits of active therapies, make this review a necessary step in evaluating the effectiveness of PE on AD-relevant measures such as physical-functional capacity, cognitive performance, neuropsychiatric symptoms, and quality of life.
The main objective was to find out if PE was able to improve, or at least maintain the variables physical-functional capacity, cognitive performance, neuropsychiatric symptoms, and quality of life, on patients suffering from AD.
The secondary objective was to provide an evidence-based recommendation of the minimum required PE to achieve benefits on the main variables physical-functional capacity and cognitive performance on AD patients.
Materials and methods
This systematic review was carried out according to the PRISMA Statement guidelines. This revision was registered in February 2021 in the PROSPERO database, with identifier CRD42021229891. A bibliographic search was carried out during the months of February to April 2021 in the databases Pubmed, Scopus, PEDro, Web of Science, CINAHL, and Cochrane Library, as well as in the grey literature, in addition to a reverse search. The search categories were based on the combination of 6 Medical Subject Headings (MeSH) terms (Alzheimer disease, Dementia Alzheimer type, exercise, exercise therapy, physical activity and sports), with Boolean operators. All these terms were chosen when searching for keywords on the platform. No language filter was applied in the search. After search these terms in combination, 30409 articles were obtained (Table 1).
* Filters: randomized controlled trial, year 2011 onwards.
Selection of studies and eligibility criteria
The search, compilation, and selection of articles was carried out by two of the authors (RCC and AAO), and the same criteria were used to select the articles based on the PICO process (Population, Intervention, Comparison, and Outcomes). The authors reviewed the title and abstract of each article independently. Then, the same procedure was followed for the full-text review, with the aim of identifying the articles of interest for the present study. If there was disagreement, a third reviewer (AMA) was responsible for resolving any discrepancies. Duplicate articles were excluded from our study.
The requirements that the studies included in the review had to meet were the following:
• Type of study: randomized controlled trials.
• Type of intervention: any type of PE-based intervention in any of its multiple modalities.
• Type of participants: patients diagnosed with AD in any of its stages.
• Outcome measures: physical-functional capacity, cognitive performance, neuropsychiatric symptoms, and quality of life.
• To gather the most up-to-date evidence on this topic, a filter was applied so that only articles published in the last 10 years were included.
• Methodological quality: studies whose methodological quality was ≥6 on the PEDro scale.
Other types of studies were excluded (reviews, cohort studies, pilot studies, study protocols, studies whose main intervention was not PE); animal studies, non-exclusive studies of AD (mixed dementias, Parkinson’s disease, mild cognitive impairment), studies in which physical-functional capacity, cognitive performance, neuropsychiatric symptoms, or quality of life were not listed as one of the outcome measures and studies with a lower PEDro score than required.
The main outcome measures in this review were physical-functional ability and cognitive performance. Physical-functional capacity is a term that encompasses the ability of people to perform daily activities independently and autonomously, including those that require physical activity (26, 27). While, cognitive performance is a wide term that measures the mental processes involved in acquiring knowledge, manipulating information, and reasoning (28). In the studies included, physical-functional capacity was included as main outcome in one study (18), as secondary outcome in another two studies (16, 17) and was not specified in the remaining three studies that measured it (29–31). In the case of cognitive performance, was included as primary outcome in one study (21), as secondary outcome in another two studies (16, 19) and was not specified in the remaining two studies which included this variable (29, 31).
Secondary measures were neuropsychiatric symptoms and quality of life. Neuropsychiatric symptoms are non-cognitive disorders common in dementia and cognitive impairment. These include various such as depression, apathy and anxiety (32). On the other hand, quality of life is defined as an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, norms and concerns (33). Both, neuropsychiatric symptoms (19, 21), and quality of life (16, 21) were secondary outcomes of the included studies.
The two reviewers (RCC and AAO) used a similar procedure to extract the data and results from each study.
The data extracted included the PICO elements: characteristics of the participants, sample size and study design, description of the interventions (protocol and type of PE and its duration), as well as the outcome measures analyzed in each article and their results. In addition, author´s data, year and diagnostic criteria for AD were extracted. Whenever data were missing, the authors of the study were contacted so that they could be provided. Articles were excluded when said condition could not be met.
Assessment of methodological quality and risk of bias
The two reviewers (RCC and AAO) independently assessed the methodological quality of the articles using the PEDro scale. Studies with a score equal to or greater than 5 were classified as having high methodological quality and low risk of bias (34).
In addition, Internal validity (IV) was also calculated (Table 2) taking into account 7 of the criteria (2, 3, 5, 6, 7, 8, and 9) in the PEDro scale. Studies with IV score ≥6 were considered to have high IV, moderate IV when 4-5, and limited IV when ≤3 (35).
Selection of studies
The searches carried out in the different databases yielded a total of 30409 articles. After filtering by search limits, 8633 articles were extracted. Many of these were discarded by means of an analysis of duplicates, resulting in 169 articles. The inclusion and exclusion criteria were then applied (except for the PEDro scale assessment), and 11 articles were deemed acceptable (9 results plus two more which was suggested to us and had not been included in the search due to its recent publication) to search for full-text analysis. Finally, 3 articles were excluded for having a PEDro score of 5 (below the required value of 6), so a total of 8 articles (16–19, 21, 29–31) were chosen (Figure 1: Flowchart).
Characteristics of the studies
All studies included in the review were RCTs published from 2011 onward. It should be noted that both Sobol et al. 2016 and 2018 (17, 19) are secondary trials to the original study, Hoffmann et al 2015 (21), and their participants are therefore the same.
Both studies by Sobol et al. (17, 19) used the sample of Hoffmann et al. (21), so the total number of participants was 562 people from 6 studies (16, 18, 21, 29–31). The sample characteristic was 52.85% men, aged between 50-90 years (75.2 ± 3.9 years), and a diagnosis of AD, of which 324 carried out a PE-based intervention while the remaining 238 were subject to other non-PE-based therapies (usual care).
Regarding the sample size of the studies, we must comment that 2 of the studies gathered the majority of the total sample, 73%, in the case of Pitkala et al. (18) 210 participants, followed closely by the study by Hoffmann et al. (21), with 200 participants. The remaining 4 studies, because both studies by Sobol et al. (17, 19) had the same sample as Hoffmann et al. (21), were studies with a smaller sample, 52 participants in the case of Enette et al. (16), and 40 and 39 participants in the cases of Vreugdenhil et al. (29) and Pedrinolla et al. (30), respectively. Finally, the study by Venturelli et al. (31) only had 21 participants.
In all studies the intervention involved performing PE in one of its modalities. Specifically, in this review two distinct forms of intervention appeared: aerobic PE (16, 17, 19, 21, 31) (144 participants) and multimodal PE (18, 29, 30), which is based on strength, balance, and aerobic PE (180 subjects).
Aerobic PE interventions were based on endurance PE through the exclusive use of a cycle ergometer (16), a combination of cycle ergometer and treadmill (17, 19, 21), or walking (31). On the other hand, intervention with multimodal PE were based on strength, balance, and aerobic programs carried out at home and in sports centers (18, 29). However, in the remaining multimodal PE study (30), multimodal PE program included aerobic and strength, but not balance PE. In 5 studies (16, 17, 19, 21, 30) the intensity of the PE was moderate, 70-80% of the maximum heart rate of the patient. In 2 of them (18, 29) the only indication was that PE was to be performed with intensity, while in the remaining one (31) participants were ordered to perform the PE at the highest possible speed.
The duration of the interventions varied between 9 weeks (16), 16 weeks (17, 19, 21, 29), 6 months (30, 31), and 12 months (18). Regarding the number of weekly PE sessions, they ranged from a minimum of 2 sessions (16, 18) to a maximum of 7 weekly sessions (29). In that interval, 4 studies (17, 19, 21, 30) involved 3 weekly sessions, and the study by Venturelli et al. (31) required 4 sessions per week to take place. In terms of session duration, the studies showed great homogeneity, with 30 minutes in 2 of the studies (16, 31), 60 minutes in 5 studies (17–19, 21, 29), and 90 minutes in the remaining study (30). All these data are specified in Tables 3 and 4.
The interventions carried out were compared with usual care and access to qualified personnel for the management of dementia (16–19, 21, 29). In the exceptional cases of Venturelli et al. (31), the control group carried out workshops on activities of daily living and music therapy, and Pedrinolla et al. (30), the control group performed cognitive therapy. These data are displayed in Tables 3 and 4.
* Abbreviations: ADCS-ADL, Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale, CAT, continuous aerobic training; CPET, cardiopulmonary exercise test; DSM, Diagnostic and Statistical Manual; IAT, intermittent aerobic training; METs, Metabolic equivalents of task; MTP, maximum tolerated power; POMA, Performance Oriented Mobility Assessment; VO2, oxygen volume. † Scores: 6MWT (more meters indicates better functional capacity), MMSE (0-30, more scores indicate better cognitive function), EMT (0-75, high score indicates better memory function), DST (0-9, high scores indicate better memory function), QoL-AD (13-52, high scores indicate better quality of life), SDMT (high score indicates more level of mental speed and attention), EQ-5D (-0.624-1, high score indicates better quality of life), ADCS-ADL (0-78, high score indicates better activities of daily living function), HAMD-17 (0-52, high score indicates more severe depression), NPI-12 (0-144, high score indicates more severe neuropsychiatric symptoms), ADAS-Cog (0-70, high score indicates worse cognitive state), TUG (less time indicates better physical function), 30-STS (more repetitions indicates better functional capacity), POMA (0-28, high score indicates better gait and balance), PPT (0-28, high score indicates better physical function), Barthel index (0-100, high score indicates more level of independence).
* Abbreviations: IADL, Lawton and Brody Instrumental Activities of Daily Living; GDS, Geriatric Depression Scale; PLM, Passive Limb Movement; FMD, Flow-mediated Dilation; VEGF, Vascular Endothelial Growth Factor. † Scores: FIM (18-126, high score indicates more independence), SPPB (0-12, high score indicates better mobility and functional capacity), FRT (more centimeters indicates better physical function), IADL (0-8, high score indicates more activities daily living independence), GDS (less scores indicate better mood), NIA (National Institute on Aging-Alzheimer´s Association).
The primary outcomes to be studied were physical-functional capacity and cognitive performance. Physical-functional capacity was assessed in 6 of the 8 studies (16–18, 29–31) in very diverse fashions, notably the 6-Minute Walk Test (6MWT, more meters indicates better functional capacity) (17, 29, 30), the Timed Up-and-Go Test (TUG, less time indicates better physical function) and the 30-Second Sit-to-Stand Test (30-STS, more repetitions indicates better functional capacity) (19, 29). This variable was also collected, to a lesser extent, through the Functional Independence Measure (FIM, 18-126, higher score indicates better more independence), the Short Physical Performance Battery (SPPB, 0-12, high score indicates better mobility and functional capacity), the Functional Reach Test (FRT, more centimeters indicates better physical function), the Physical Performance Test (PPT, 0-28, high score indicates better physical function), the 10- and 400- Meter Walk Tests, and the Astrand Cycle Ergometer Test.
On the other hand, cognitive performance was observed in 5 of the 8 included studies (16, 19, 21, 29, 31), and it was measured using different scales, namely the Mini Mental State Examination (MMSE, 0-30, high score indicates better cognitive state) (16, 21, 29, 31) and the Alzheimer Disease Assessment Scale (ADAS-Cog, 0-70, high score indicates worse cognitive state) (21, 29). Additionally, other scales such as the Symbol Digit Modalities Test (SDMT, high score indicates better level of mental speed and attention), the Digit Span Test (DST, 0-9, high score indicates more memory function), and the Episodic Memory Test (EMT, 0-75, high score indicates better memory) were also used.
Neuropsychiatric symptoms (19, 21) and quality of life (16, 21) were chosen as secondary study variables, with both present in 2 of the 8 studies included in this review. Regarding neuropsychiatric symptoms, these were measured through the Neuropsychiatric Inventory (NPI-12, 0-144, high score indicates more severe neuropsychiatric symptoms ) (19, 21) and Hamilton Depression Rating Scale (HAMD-17, 0-52, high score indicates more severe depression) (21). Finally, quality of life was measured through the Quality of life Alzheimer’s Disease (QoL-AD, 13-52, high score indicates better quality of life) (16) and the European Quality of Life (EQ-5D, -0.624-1, high scores indicates better quality of life) scales (21).
Risk of bias and methodological quality assessment
The clinical trials selected in this review scored a maximum of 8 and a minimum of 6 on the 10 scoring items on the PEDro scale. Of these 8 articles, 5 showed a moderate IV score (16–19,21) and the remaining 3 showed a score of limited IV (29–31). These data appear in Table 2.
Main results: physical-functional capacity and cognitive performance
Physical-functional capacity was measured in 6 of the 8 articles that compose this review (16–18, 30, 31).
Enette et al. (16) evaluated the physical-functional capacity with 6MWT in 52 participants who were randomized into 3 groups, in which 2 performed aerobic PE, either continuously (n=14) or intermittently (n=17), while the control group (n=21) received usual care and briefings. Measurements were made pre- and post-intervention. After 9 weeks of training the physical-functional capacity improved in both intervention groups (continuous PE +28 meters, 4.7%, p=.005; intermittent PE +36 meters, 7.2%, p=.007) compared with baseline levels. There were no significant intergroup differences between both intervention groups (p>0.05).
Sobol et al. (17) used the following tests to measure this variable: TUG Test, Astrand Cycle ergometer test, 30 STS, and 10-400 MWT. The sample consisted of 200 participants, randomized into either an intervention group (n=102) that performed aerobic PE using a cycle ergometer and treadmill, and a control group (n=88) who received usual care and access to clinical staff specialized in dementias. The variables were observed pre- and post-intervention. After 16 weeks of training, significance was not reached between groups or at baseline.
Venturelli et al. (31) used the PPT and 6MWT for the measurement of physical-functional capacity. In this case, the sample consisted of 21 participants, randomized into two groups. One group received aerobic PE (n=11) walking at the maximum possible speed, and the control group (n=10) took part in activities such as bingo, sewing, and music therapy. Pre- and post-intervention variables were measured. After 6 months of intervention statistically significant results (p<.001) were observed in favor of the intervention group in an intergroup comparison, while the control group not only did not improve but drastically worsened (-29,4%; p<.05). There were also significant changes in the physical-functional capacity of the intervention group compared with baseline values in 6MWT (+20%; p<.001).
Pitkala et al. (18) used the FIM and SPPB to measure this variable. Their sample size was 210 subjects randomized into 3 groups, of which 2 received a PE intervention, one at home (n=70) adapting the intensity to the possibilities of each patient, and another a strength-, balance-, and endurance-based PE program (n=70) in sports centers. The control group (n=70) received usual care as well as nutrition and PE advice. The study collected measures at the beginning as well as 3 months, 6 months, and 12 months post-intervention). After 3 months of intervention the physical-functional capacity decreased in all 3 groups. Only after 6 months significant differences appeared in favor of the intervention groups, in the intergroup comparison at FIM score (Home PE -6.5, 95% CI; Sports center PE -8.9, 95% CI; Control -11.8, 95% CI). Said differences were maintained until the 12-month mark. After one year of intervention all groups showed deterioration, which was however greater for the control group (p=.003) than for the PE groups (intergroup). A protective effect could therefore be attributed to PE regarding the two groups that performed PE. There were no significant differences in SPPB score.
Vreugdenhil et al. (29) measured the physical-functional capacity through the TUG Test, the 30 STS, and FRT. Their sample included 40 participants randomized into 2 groups: one received a strength-based PE intervention (n=20) in addition to 30 minutes of walking; the control group (n=20) received their usual treatment. Measurements were made pre- and post-intervention. At the end of the 16 weeks of intervention the group that practiced PE showed improvements in physical-functional capacity when compared with the control group (TUG -2.9 seconds, p=.004; STS +2,7 p<0.001; FRT +4,2 cm, p=0.032).
Pedrinolla et al. (30) evaluated this variable using 6MWT and PPT. Their sample included 39 participants randomized into 2 groups: one performed high-intensity aerobic and strength training (n=20); while the control group (n=19) performed cognitive therapy through multi-modal stimuli (visual, verbal, auditive, tactile). Measurements were made pre- and post-intervention. After 6 months significant post-treatment differences in 6MWT and PPT were found between groups (6MWT: 91.3 m, p=0.001 and PPT: 2.0 points, p=0.039) and compared to baseline (6MWT: 70.5 m, p=0.002 and PPT: 2.5 points, p=0.023) in favor of the PE group. No differences were found for the control group in both tests, neither intergroup nor compared to the baseline.
Cognitive performance was analyzed in 5 of the 8 studies in this review (16, 19, 21, 29, 31).
Hoffmann et al. (21) evaluated this variable using MMSE, ADAS-Cog, and SDMT. Their sample consisted of 200 participants randomized into 2 groups. One underwent aerobic PE (n=108), while the control group (n=82) received their usual treatment. The study variables were observed pre- and post-intervention. After 16 weeks the results showed a difference of 2.5 points in SDMT in favor of the intervention group (95% CI) when compared with individuals in the control group. There were no significant intergroup differences in MMSE and ADAS-Cog. Significance was not reached for this variable versus baseline in either group.
Sobol et al. (19) used SDMT to observe cognitive performance. They based their study on the design and intervention described by Hoffmann et al. (21), only with a reduced sample of 55 of the 200 original participants. Variables were measured pre- and post-intervention. After the 16 weeks of intervention a direct relationship was established between a higher amount of PE and a better score in cognitive performance in intergroup SDMT values, with a difference of 4.2 points (p=.01; 95% CI) between groups in favor of the intervention group.
Enette et al. (16) assessed this variable using MMSE, DST, and EMT. At the end of the 9 weeks of training significant differences were found in MMSE only in favor of the group that performed aerobic PE continuously compared with the group that performed aerobic PE intermittently (continuous PE +11,1% vs. intermittent PE -5,6%, p=.04). Significance was not reached for the other tests against the baseline or in intergroup comparisons.
Vreugdenhil et al. (29) used MMSE and ADAS-Cog for cognitive performance measurement. At the end of the 16 weeks of intervention the group that performed PE showed an improvement of 2.6 points in MMSE (p=.001) and a decrease (implying improvement) in ADAS-Cog of 7.1 points (p=.001) compared with the control group.
Venturelli et al. (31) assessed this variable using MMSE. At the end of 6 months of intervention statistically significant results (p<.05) were observed in favor of the intervention group in an intergroup comparison, where control group decrease MMSE score -47%, while intervention group had a lower decline of -13%.
Secondary outcomes: neuropsychiatric symptoms and quality of life
Neuropsychiatric symptoms were measured in 2 of the 8 studies in this review (19, 21).
Hoffmann et al. (21) used two scales, NPI-12 and HAMD-17. At the end of the 16 weeks of intervention there were significant changes in the group that performed aerobic PE at NPI-12 with a -3,5 points (p=.002; 95% CI) compared with control group. Significance was not reached intergroup for HAMD-17, nor against baseline for HAMD-17.
Sobol et al. (19) used the NPI-12 scale to measure this variable. After 16 weeks of intervention there were intergroup differences in favor of the group that performed PE at NPI-12 with -3.4 points (p=.007; 95% CI), compared with control group, suggesting a positive association between PE and an improvement in neuropsychiatric symptoms. There were no intragroup differences in any of the groups for this variable.
Quality of life was measured in 2 of the 8 studies that make up this review (16, 21).
Enette et al. (16) used the QoL-AD questionnaire. At the end of the 9 weeks of training significant changes were found only in favor of the group that performed aerobic PE continuously compared with baseline (+5.9%; p=.008). Furthermore, this same group showed significant differences compared with the control group for this variable (p=.002). Significance was not reached between both PE groups.
Finally, Hoffmann et al. (21) measured quality of life using EQ-5D. After 16 weeks of intervention there were no intragroup or intergroup differences in any of the groups for this variable.
Life expectancy has increased in recent decades due to advances in areas such as medicine, nutrition, and lifestyle. In an indirect manner, this has brought about an increase in the quality of life. However, this increase in life expectancy has also brought negative consequences such as an increase in degenerative diseases, among which neurodegenerative diseases stand out. This diseases are characterized by high oxidative stress processes, with the presence of inflammatory markers, such as cytokines, for instance (36, 37). Patients with AD have low blood and brain BDNF levels from the early stages of the disease, and BDNF levels are positively correlated with cognitive function (38). These inflammatory markers can be modulated by the action of PE, capable of improving some pathological characteristics of AD (37) such as increased clearance of amyloid and tau proteins (25), in addition to promote the release of the BDNF (16), which favors the processes of neurogenesis, synaptogenesis and dendritogenesis, which induces benefits on cognitive function and brain structure (39). Moreover, PE protects against AD due to its effects on hippocampal volume and cerebral perfusion level (40, 41).
Due to the direct benefits derived from regular PE practice (42, 43) it has been suggested that its potential to affect the physical-functional capacity and cognitive performance in those who suffer from AD should be explored, since these variables deteriorate especially in such individuals (18).
AD has been characterized not only by the cognitive impairment it causes, but also by physical-functional impairment. Such physical-functional decline has also been observed during the early stages of AD (44). Therefore, one of our main variables of this systematic review was physical-functional capacity. Performance losses in motor tasks has been observed in the early stages of AD, and has been associated with a decline in functional capacities, greater disability, and risk of falls (44). As stiffness increases with the progression of the disease, walking speed decreases. This decrease in walking speed decrease is in turn magnified by sarcopenia and progressive weight loss (45). On the other hand, the beneficial effects of PE in several domains of physical-functional capacity have been stated (46, 47). Six of eight articles included in this review (16–18, 29–31) evaluated physical-functional capacity. According to these studies, all PE groups showed improvements in this variable when compared with the controls. The only exception were those of Pitkala et al. (18), in which both groups deteriorated, although to a lesser extent in the intervention group, and Sobol et al. (17), in which there were slight improvements in favor of PE group that did not reach statistical significance. In the case of Venturelli et al. (31), these results reached greater significance, as the intervention group increased their physical-functional capacity while the control group saw it drastically decreased. Interestingly, the only study that showed no improvement (18), is the one where the intervention was longer (12 months). This could be due to an adaptation to the load volume, as it was not increased throughout the testing period, while in the case of Pedrinolla et al. (30) the load was increased by 5% every 4 weeks for aerobic exercise and 5% for strength exercise when participants were able to complete 12 repetitions of each set easily. The effect of PE could therefore be diluted as the intervention progresses, as observed in studies with very slow progressions or loads maintained over time in older adults (48, 49). Furthermore, in the case of Pitkala et al. (18) exact measurements were not used to determine the intensity at which the PE was performed (weight, rest, or load volume were not specified). Besides, Venturelli et al. (31) found that the greatest intergroup improvements occurred when participants were asked to walk at the highest possible speed. This could be due to the similarity between the exercise and the test used (6MWT), as this test consist on also walking at the highest possible speed. This similarity could considerably improve the test scores, as shown by previous studies (50, 51). For all this, and due to the level of evidence of the studies that include the physical-functional capacity variable, 3 of them with a limited level of evidence (29–31) and another 3 with a moderate level of evidence (16–18), we could say that there is moderate-limited evidence that supports the practice of PE to improve physical-functional capacity in patients with AD.
Due to its neurodegenerative nature, AD has been shown to cause progressive impairments of cognitive performance affecting memory, executive function, visuospatial skills, and language (52). PE has been shown to slow down the progress of cognitive impairments and even to improve cognitive abilities and brain health, both at the functional and structural levels (53). This could be due to the proven ability of PE to modulate the gene expression of nerve growth factor and neurotrophic factor (54), showing improvements in data processing speed, executive functions, and memory (55, 56). In our review, this variable was assessed in 5 out of 8 studies (16, 19, 21, 29, 31), with 4 reporting gains in the intervention groups when compared with the controls, except Venturelli et al. (31), which both groups deteriorated, although to a lesser extent in the intervention group. This could suggest that those who perform PE would experience beneficial effects on their cognitive performance, as remarked in the study by Sobol et al. (19). Besides, similar findings have been reported in other neurodegenerative diseases (57, 58). In Enette et al. (16) these differences were highly significant, but only occurred for individuals who undertook aerobic PE in a continuous manner, and not so with those who performed it intermittently, although they also improved in comparison with the control group. This difference between PE interventions could be due to the intermittent exercise intervention being insufficient to produce changes in cognitive performance (6 series consisting of 1 minute of high-intensity PE and 4 minutes of active recovery). Other systematic reviews have reported that aerobic PE was able to induce slight improvements in cognitive performance through longer PE sessions and longer intervention periods (55, 59). Therefore, we could mention that there seems to be moderate-limited evidence that PE is capable of increasing or slowing down cognitive performance in patients with AD, according to the level of evidence of the articles that measure this variable, 2 of them with a limited level of evidence (29, 31), and the remaining 3 with a moderate level of evidence (16, 19, 21).
These results agree with the study by Valenzuela et al. (60) since they suggest that PE can mitigate cognitive decline and improve physical function even though the pathophysiology of AD has already been established.
In addition to losses in physical and cognitive performance, AD patients exhibit a series of neuropsychiatric symptoms with an enormous impact on their own quality of life and that of their caregivers/relatives. During the evolution of AD, some neuropsychiatric symptoms such as agitation, depression, hallucinations, delusions, and other psychopathological changes cause great suffering to patients and their environment, in addition to increased socioeconomic costs (61). Although PE has been able to produce benefits in the neuropsychiatric and depressive symptoms of patients suffering from AD (21), engaging in PE programs poses a great challenge for these patients because their anxiety, sadness, anger, and behavioral disturbances may become really difficult to manage (31). In this review, neuropsychiatric symptoms were observed as a variable in 2 of the 8 studies (19, 21). In both studies the intervention groups experienced significant improvements when compared with the control groups. However, it must be noted that Sobol et al. (19) was a secondary study with a reduced sample of the original study by Hofmann et al. (21), with the intervention, intensity, and follow-ups remaining similar. Also, the differences between both reviews could be attributed to the fact that participants in the control group displayed more neuropsychiatric symptoms at baseline than those in the intervention group (21). However, despite the unexpected nature of this finding, PE was able to ameliorate the symptoms. While other studies have found similar findings (62, 63), that of Rolland et al. (51) failed to find any beneficial effects. Both review studies that measure this variable have a moderate level of evidence (19, 21), so we could say that there is moderate evidence that PE can reduce the neuropsychiatric symptoms that AD patients may experience.
Due to the effect of AD on the hippocampus and on cell death and brain atrophy, the management of the simplest daily tasks are greatly affected. Some abilities become effectively lost and cause significant reductions in the quality of life of patients as well as caregivers and relatives (64). For this reason, quality of life was chosen as a secondary variable for the purposes of this review. Some studies have shown that PE has the potential to alleviate some symptoms of dementia and improve AD biomarkers, thus bringing about improvements in quality of life (65, 66). Two of the 8 studies in this systematic review assessed this variable (16, 21). In that regard, Enette et al. (16) found significant improvements in the group that performed continuous aerobic PE. Despite both intervention groups improving compared with the control group, gains were greater in the continuous aerobic PE group. However, Hoffmann et al. (21) found similar results for both the PE and the control group. This discrepancy is surprising given the similarity between the interventions administered to both PE groups. One possible explanation may lie in the fact that in Hoffmann et al. (21) initial quality of life values were very high, and their sensitivity to change could therefore be reduced. The literature reviewed supports the practice of PE to improve the quality of life in similar populations (67, 68). Due to the moderate level of evidence of the 2 review studies that analyze quality of life (16, 21), we can affirm that PE could improve or at least maintain quality of life in patients with AD.
Adressing PE modality, it seems that strength PE (weight lifting, for example), continues to be the great forgotten despite its enormous therapeutic potential in the elderly. This works remarkably against the risk of AD and general cognitive performance through the release of myokines, in addition to having a protective effect against cardiovascular diseases (24). There is strong evidence for the positive impact of endurance PE on cognitive performance in AD patients, but in the case of strength PE, these effects remain unclear (69).
However, recent studies using strength PE have resulted in higher and longer lasting concentrations of irisin than endurance PE produces (70). Irisin is a hormone produced by muscle tissue in response to PE, and is a myokine capable of crossing the blood-brain barrier and stimulating hippocampal neurogenesis through increased BDNF expression (60). Due to its effect on mental health, a potential effectiveness of strength PE in preventing AD and improving cognitive performance in already affected patients is suggested. In addition, strength PE prevents the activation of the NLRP3 inflammasome, which plays a fundamental role in the pathogenesis of AD (60). Along these lines, there are studies that observe that muscle strength and mass are inversely associated with cognitive impairment and the risk of suffering from AD (71, 72). Other studies report a connection between sarcopenia and greater cognitive impairment (73), so strength PE could be a solution to combat cognitive impairment and functional capacity loss suffered by AD patients. In our review, only one of the 8 studies measured cognitive performance using an intervention based on strength PE, although it also included endurance PE, resulting in improved cognitive performance post-intervention (29). In the remaining 4 studies that observed this variable, only endurance PE was performed (16, 19, 21, 31), achieving an improvement or at least a slowdown (31) in cognitive performance.
Today there is a greater body of evidence on endurance PE, but it is necessary to investigate strength PE due to its enormous therapeutic potential in patients with AD, both in terms of cognitive performance and physical-functional capacity. However, the need to include proposals based on PE, regardless of the type, in these populations seems unquestionable.
Regarding the optimal dose of PE, we must first emphasize the intensity at which the exercise is performed. This is due to the role of lactate, whose functions appear to include the promotion of angiogenesis and neurogenesis in the hippocampus. Additionally, this metabolite also appears to have beneficial effects on AD-related neuroinflammation (60).
Therefore, high-intensity PE would produce higher lactate levels than moderate PE, despite the fact that the latter is often used in this type of patients, with doses close to 30 minutes (60), as it occurs in several studies in this review (16, 17, 19, 21, 30).
High-intensity PE has also been shown to produce a greater increase in BDNF, compared to moderate-intensity PE (72, 74). In many cases, high-intensity PE is not used in these populations; however, this dose of PE is an advisable option in these populations (60).
On the contrary, it seems that the use of high-intensity PE for long periods of time, at least 3 months, could produce a pro-inflammatory state compared to moderate-intensity PE (75). Due to this, it would be interesting for future studies to compare both intensities of PE in the development of AD (60).
Continuing with the optimal dose of PE, it seems that at least 9 weeks of moderate-intensity aerobic PE, a minimum of 2 weekly sessions, and lasting 30 minutes per session, are required to achieve observable benefits in the main study variables physical-functional capacity and cognitive performance, as shown by Enette et al. (16) in his studio. However, beneficial results were also found for physical-functional capacity and cognitive performance in the other review studies that measured both variables, although the interventions were longer, 16 weeks in the case of Vreugdenhil et al. (29) and 6 months in the case of Venturelli et al. (31).
Despite all this, we must be aware of the difficulty of establishing an optimal dose for these patients due to the number of different parameters that PE may present, such as the number of weekly sessions, total duration of the program and session, rest between series and intensity at which it is performed.
Regarding the volume of PE, the weekly training volume was observed, multiplying the number of weekly sessions by the time of each session in minutes. The results in the review studies were very heterogeneous, from a weekly PE volume of 60 minutes by Enette et al. (16) up to 270 minutes per week in the study by Pedrinolla et al. (30). There were two studies that had a similar volume of 120 minutes per week, in the case of Venturelli et al. (31) and Pitkala et al. (18). Increasing this volume we found the study by Hoffmann et al. (21) and their 2 secondary studies, Sobol et al. (17, 19), in which the weekly volume was 180 minutes per week. Finally, in the study by Vreugdenhil et al. (29) 210 minutes of aerobic PE per week were specified, but the remaining time spent performing 10 strength and balance exercises was not included, so we were unable to specify the exact weekly volume. After analyzing the weekly PE volume in the review studies, and the results obtained in the study variables, no direct relationship has been observed between the PE volume and the improvement of the variables physical-functional capacity, cognitive performance, symptoms neuropsychiatric and quality of life. However, these data seem to show us that a minimum of 60 minutes of aerobic PE per week is required (16) in patients with Alzheimer’s to achieve observable benefits in the main variables physical-functional capacity and cognitive performance.
Another important aspect to comment was the baseline cognitive status of the review patients. In our study, the patients showed great heterogeneity in MMSE, from 10 to 30 points, in the case of Hoffmann et al. (21), some patients already had the highest score prior to the intervention, so for some of them showing improvements was impossible or very difficult. In addition, also due to the wide age range of the participants, from 50 to 90 years old, the means and ranges in the MMSE score varied on many occasions depending on their age, due to as a consequence of age and processes that underlie cognitive ability decreases during aging, as some studies indicate, even more in patients suffering from neurodegenerative diseases such as AD (76 ,77). This relationship was observed in both studies in which there were younger individuals, in the case of Hoffmann et al. (21), the mean of the MMSE participants was high, 24 points, and 22 points in the study of Vreugdenhil et al. (29).
On the other hand, in the case of studies with older participants, such as Venturelli et al. (31) (mean age 84 years) the mean MMSE score was between 12 and 13 points. Finally, we could also see this relationship in those studies with a sample whose participants had ages in a more intermediate range of old age, such as Enette et al. (16), which gathered individuals between 68-84 years old whose MMSE score was 18-21 points on average, or the case of Pitkala et al. (18), which selected individuals older than 65 years, whose mean MMSE score was 17.7-18.5, these results being also moderate.
Regarding follow-ups, studies featured a high degree of homogeneity since they all adhered to the premise of pre- and post-intervention measurement, with the exception of Enette et al. (16) which measured the variable level of BDNF in plasma 4 weeks post-intervention, and Pitkala et al. (18), which was the only review study that measured the variables during the intervention (at 3 and 6 months). In addition, they measured the uses and costs of social and health services up to 1 year after the intervention or death of the individual. However, none of these variables were included among the main ones.
Another important aspect, was the adherence to PE programs in the reviewed studies. Mainly, adherence to PE programs was quite high, highlighting the study by Pedrinolla et al. (30), where adherence to the sessions was total, closely followed by Enette et al. (16) and Venturelli et al. (31), with 94.2% and 93.4%, respectively, of PE sessions completed. Then, we find the study by Pitkala et al. (18), with 84.3% of PE sessions completed, and finally the study by Hoffmann et al. (21) and their secondary studies Sobol et al. (17, 19), in which adherence was lower, 76% of the group that performed PE completed at least 80% of the sessions. In the remaining study by Vreugdenhil et al. (29) no data on adherence to PE sessions were provided. These data could underline the importance of adherence by these patients to PE programs, since in studies with less adherence there were worse results in the observed measures, as in the case of Pitkala et al. (18) where the physical-functional capacity slightly deteriorated in the participants who performed PE, and in the study by Hoffmann et al. (21), in which the quality of life did not show changes in the PE group compared to the control group.
Exercise was monitored and supervised in all the studies of this review. The increased dependency of AD patients makes adhering to any PE program a challenge (22). Therefore, all programs with the potential to benefit AD patients must be properly supervised and monitored by professionals able to face the many difficulties and/or alterations of participants.
To summarize the effects of PE on the variables observed, it seems that aerobic PE or multimodal PE can improve physical-functional capacity and cognitive performance compared to the control group in the studies that evaluated it. In the case of secondary variables, aerobic PE seems to be able to reduce neuropsychiatric symptoms and improve, or at least preserve, quality of life with respect to the control group, as shown by the studies reviewed.
This systematic review is subject to several limitations. In the first place, the high degree of clinical and statistical heterogeneity among the studies prevents a meta-analysis from being carried out, given the considerable differences in intervention times, protocols, and variable measurement. Secondly, the absence of follow-ups after the completion of the intervention has made it impossible to verify whether the beneficial effects of PE on AD patients are maintained in the short, medium, or long term. Six of the 8 studies included in this systematic review featured an original sample. However, in both studies by Sobol et al. (17, 19) the sample was the same used by Hoffmann et al. (21). Another limitation became apparent when evaluating multimodal PE due to the scarcity of related studies involving individuals with AD. More high-quality scientific production is required in order to properly assess the effect of strength-based PE and other modalities on similar populations. Despite the fact that PE is currently employed as a therapy for patients with neurodegenerative diseases, we believe that more work is required to strengthen the evidence for similar interventions, so that the optimal dose and modality can be uniformly established for each specific individual. Furthermore, study designs such as the ones featured in this review make it patently difficult to blind therapists and participants, particularly when the control group does not engage with PE in any form.
This systematic review found moderate to limited evidence that aerobic physical exercise on its own or combined in a multimodal program that also includes strength and balance exercise can be a useful tool in the management of patients with Alzheimer’s disease with the aim of maintaining and/or improving physical-functional capacity and cognitive performance. In addition, this review found moderate evidence of the positive impact that aerobic physical exercise could have in reducing neuropsychiatric symptoms and improving quality of life in patients with Alzheimer´s disease.
Currently, the majority of evidence is on aerobic PE, but it is necessary to investigate strength PE due to its enormous therapeutic potential in patients with AD, both in terms of cognitive performance and physical-functional capacity.
As general recommendation, it seems that at least 9 weeks of moderate-intensity aerobic PE, a minimum of 2 weekly sessions, and lasting 30 minutes per session, are required to achieve observable benefits in the variables physical-functional capacity and cognitive performance on AD patients.
Ethical standards: Not applicable.
Conflict of interest: The authors report no conflicts of interest.
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