A systematic review of lifestyle-based interventions for managing Alzheimer's disease: Insights from randomized controlled trials

Abstract

Background

Alzheimer's disease (AD) presents a significant challenge in healthcare, prompting exploration into non-pharmacological interventions to complement traditional treatments.

Objective

This systematic review explores the efficacy of lifestyle-based interventions in managing AD.

Methods

A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus between 2018 and 2023, selecting randomized controlled trials examining factors such as exercise, diet, stress, and cognitive training in AD patients.

Results

The review revealed physical exercise as the predominant non-pharmacological intervention, accompanied by dietary modifications, cognitive training, and therapies such as mindfulness and music. While exercise demonstrated improvements in quality of life, its cognitive benefits were limited. Modified diets, such as Atkins and ketogenic, displayed inconsistent effects on cognitive function but influenced other health-related parameters. Additionally, probiotic therapy and novel cognitive training technologies were explored.

Conclusions

Despite some interventions showing promise in enhancing cognitive function and slowing disease progression, uncertainties remain regarding the dose-response relationship, underlying mechanisms, and potential synergistic effects. Moreover, consideration of genetic and sex-based disparities is warranted. This synthesis underscores the need for further research to elucidate the nuances of non-pharmacological interventions in managing AD effectively.

PROSPERO registration number

CRD42023432823

Keywords

Alzheimer's disease diet exercise lifestyle mindfulness music therapy probiotics

Introduction

The progressive growth and aging of the population are expected to lead to a continued increase in Alzheimer's disease (AD) cases. AD is a progressive neurodegenerative disorder that causes neuronal damage and cognitive impairment, leading to memory loss and language problems. As the disease advances, it affects basic bodily functions such as walking and swallowing, significantly reducing the quality of life. AD typically affects adults over 65, individuals with a first-degree relative diagnosed with AD.¹ Risk factors include age, sex, genetics, and lifestyle factors such as physical inactivity, poor diet, chronic diseases, and pollution.²

Current treatments are limited, with cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists offering minimal symptom relief. Consequently, research is exploring alternative treatments, including non-pharmacological therapies targeting modifiable risk factors. Studies suggest that physical exercise can prevent and delay neurodegenerative diseases and enhance cognitive function in AD patients.^3,4 Diets such as the Mediterranean diet can also play a crucial role in preventing AD,⁵ and various nutrients and nutraceuticals, such as vitamins, polyunsaturated fatty acids, and antioxidants, show benefits in AD.⁶ Other therapies include memory training, ginkgo biloba, acupuncture, yoga, and music.^7,8

Randomized controlled trials (RCTs) are the gold standard for establishing the efficacy of interventions. Given the rising prevalence of AD and the gaps in understanding its modulatory factors, further research is essential to identify effective interventions. This study aims to systematically review non-pharmacological treatments, particularly lifestyle-related RCTs, as adjunctive therapies for AD. Given the rising prevalence of neurodegenerative disorders, particularly AD, and the ongoing gaps in understanding the disease's modulatory factors, further research is imperative to identify interventions capable of significantly mitigating its symptoms and progression.

Methods

Our systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist recommendations.⁹ The review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database in June 2023 (registration number CRD42023432823).

Search strategy

In October 2023, we conducted a thorough literature search in the PubMed, Web of Science, and Scopus databases to identify relevant articles published in English and Spanish within the last 5 years (2018–2023). The revision focuses on the last five years to provide a more up-to-date and practical perspective, evaluating the latest and most effective lifestyle strategies for managing and preventing AD. Grey literature was not included in this review due to its lack of peer review and standardized methods. We did not select ClinicalTrials.gov because the quality and completeness of the data reported in the database may lack the detailed methodological descriptions necessary for inclusion in a systematic review. Additionally, the information on ClinicalTrials.gov has not undergone peer review and often includes preliminary or interim results. The search utilized keywords connected by Boolean connectors and focused on lifestyle interventions for managing AD, meaning AD syndrome with or without supporting biomarker evidence, including physical exercise, diet, medical foods, stress control therapies, sleep improvement strategies, gaming, and new technologies that can be implemented in a patient's daily life without the need for professional support (Supplemental Material). If a study included a group of patients with mild cognitive impairment in addition to the AD group, the results of the comparison between the two patient groups were included in the tables. The review process was conducted using Covidence systematic review software (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia) available at http://www.covidence.org (2023–2024). Initially, articles (titles and abstracts) were screened by two independent reviewers based on the eligibility criteria. In cases of disagreement regarding article inclusion, a third researcher reviewed the article's eligibility for inclusion or exclusion.

Eligibility/exclusion criteria: participants, interventions, outcomes, study design

The research question for this systematic review was ‘What strategies related to lifestyle factors, including exercise, diet, stress management, and cognitive training can be useful in managing symptoms of AD? In pursuit of that question, inclusion criteria were established based on the PICOS criteria¹⁰ (Table 1).

Table 1.

PICOS table for studies inclusion.

Population	Adult Alzheimer's disease patients Men and women
Intervention	Non-pharmacological approaches within the realm of lifestyle, such as physical exercise, diet modifications, cognitive training, mindfulness, music, etc.
Comparison	Include either a placebo or control group (parallel group studies design) or experimental condition (cross-over studies design)
Outcome	Any parameter related to cognition and/or health status
Study design	Randomized controlled trials

Only articles written in English and Spanish were considered for inclusion in the review. We excluded in vitro studies, research conducted on animal models, studies centered on caregivers, pharmacological treatments, studies assessing the feasibility of an intervention, meta-analyses, reviews, or interventions requiring the assistance of technical staff. For synthesis, studies were grouped into the following categories: ‘exercise interventions’, ‘supplements and diets’, ‘cognitive training’ and ‘other related lifestyle interventions’.

Data extraction

Data extraction was independently conducted by two reviewers, encompassing various aspects of the included studies. Details regarding baseline population characteristics, intervention specifics, study variables, measurement methods employed, and primary outcomes were extracted. Additionally, study characteristics such as study design, RCT type, and blinding method were also documented. To ensure the precision of the extracted data, a third reviewer meticulously reviewed the information for any potential errors or inconsistencies. The following information was collected for all studies: study objective, patient characteristics including AD severity, mean age, and percentage of male subjects, number of study groups and sample size for each group, intervention details including frequency of administration, intervention duration, and key results. If the information required was not specified in the text, attempts were made to contact the authors of the manuscript to obtain it; when no response was received, this lack of information is presented as ‘not specified’ in this manuscript.

Risk of bias assessment

The potential for bias was assessed using an expanded version of the Jadad scale employed previously in systematic reviews of AD drug trials.¹¹ This scale evaluates aspects of internal validity, including the quality of randomization, double-blinding, participant withdrawals, description of inclusion and exclusion criteria, methods for assessing adverse effects, and the statistical analysis employed. Each item answered ‘yes’ earns one point, while each ‘no’ response receives zero points. Additionally, one point is deducted if the randomization method or double blinding is deemed inappropriate. Given the challenge of blinding dietary interventions, studies employing single blinding were assigned half a point, as previously described.¹² The total score for each article was calculated by summing the score of each item, ranging from 0 to 8. Studies scoring 0 to 3 were classified as low-quality, while those scoring 4 to 8 were categorized as high-quality.¹²

Results

Study inclusion

The search strategy yielded a total of 20,506 references, with 20,500 retrieved from Web of Science (7522), Scopus (6997), and PubMed (5987) (Figure 1). Of these references, 11,558 were removed due to duplicates, and 8942 underwent title and abstract screening by two independent reviewers, with discrepancies resolved by a third reviewer. A total of 278 studies underwent full-text review, and 198 were subsequently excluded. The primary reasons for exclusion included not being an interventional study (n = 70), inappropriate study population (n = 43), non-compliance with the experimental design of an RCT (n = 36), intervention not related to lifestyle factors (n = 30), type of article (protocol paper, conference paper, corrigendum, etc.) (n = 15), non-English language (n = 3), and one article has been excluded due to retraction during the reviewing process. Ultimately, 80 studies were included in the review (Figure 1).

Figure 1.

PRISMA flow diagram.

Characteristics of the included trials

The summarized characteristics and objectives of all selected studies in the systematic review are presented in Tables 2-5. Among the various lifestyle interventions for AD patients (Figure 2), physical exercise has been the subject of the highest number of RCTs (n = 40) (Table 2), followed by dietary interventions, including complete diets or nutritional compounds (n = 24) (Table 3). Additionally, three studies investigated the combined effects of physical exercise and cognitive training,^23,30,33 one study investigated the combination of exercise and visual stimulation,³⁵ photobiomodulation,³² and a third explored the combination with shiatsu, applying pressure to specific areas of the body, also known as acupressure²⁷ (Table 2). No studies were found that addressed the combined treatment of exercise and dietary intervention. Cognitive training utilizing new technologies such as computer-based programs or virtual reality was also identified during this review^77–84 (Table 4). Furthermore, the category of ‘Other types of interventions’ encompassed less-explored approaches, including mindfulness,^86,92 music therapy,⁸⁷ or shiatsu techniques,²⁷ grounding,⁹⁰ oral health,⁸⁵ companion animals,⁹³ light-based intervention⁸⁸ and electrical massage⁸⁹ (Table 5).

Figure 2.

Lifestyle interventions in Alzheimer's disease.

Table 2.

Exercise-related studies.

Author/Year of publication	Primary Outcome/s	Secondary Outcome/s	Treatment group (TG)/Age/Sex (% men)	Control group (CG)/Age/Sex (% men)	Number of groups and sample size	Intervention and number of times administered	Duration of the intervention (weeks)	Results
Angiolillo 2023¹³	Global cognitive function	Executive functions, verbal memory, visual spatial, attention and processed speed abilities, quality of life, independency daily living	Mild to moderate AD/78.89 ± 6.68/33%	Mild to moderate AD/78.92 ± 8.04/38%	2; TG = 9; CG = 13	TG: reality orientation therapy, music therapy, motor, proprioceptive, and postural rehabilitation (2/w) + Nordic walking training (60 min) CG: reality orientation therapy, music therapy, motor, proprioceptive and postural rehabilitation (2/w)	96	Improvements in cognitive domains like visual-spatial reasoning abilities, verbal episodic memory, selective attention, and processing speed
Ben Ayed 2021¹⁴	Cognitive function (attention, working memory and problem solving)		Moderate AD/n.s./51%	Moderate AD/n.s./51%	3; EG =27; CG = 26; CEG = 26	TG-EG: aerobic exercise program 1/w(20 min)TG-CEG: simultaneously exercise training (pedaling) while resolving cognitive games.CG: not perform any exercise but read	n.s.	Participants’ attention in EG and CEG improved in comparison with CG.
Cezar 2021¹⁵	Muscle strength, mobility and functional performance and capacity		Mild to moderate AD/79.75 ± 5.87/12.5%	Mild to moderate AD/79.75 ± 5.87/12.5%	2; TG = 20; CG = 20	TG: individual exercise session/3/w(60 min);CG: usual activities	16	Home intervention decreases the risk of falls, and improves strength, and functioning.
Chen 2019¹⁶	Feeding and eating execution		AD/82.7 ± 8.4/30%	AD/81.0 ± 8.1/26.7%	2; TG = 30; CG = 30	TG: hand exercises/ 3/w(30 min);CG: daily routine	24	Significant increase in autonomous eating and food intake
Chortane 2022¹⁷	Motor function	Lipid profile, creatinine, hepatic enzymes, electrolytes	Mild to moderate AD/85 ± 3/30%	Mild to moderate AD/85 ± 3/30%	2; TG = 11; CG = 9	TG: mobility, posture, and balance exercises/2/w (60 min)CG: usual activities	12	The intervention group improved gait speed, balance, and walking parameters while biochemical parameters (lipid profile, creatinine, hepatic enzymes, electrolytes) were not affected
de OliveiraSilva 2019¹⁸	Global cognition	Executive function and mobility	AD/81.22 ± 8.88/61.54%	AD/77.54 ± 8.05/21.4%	2; TG = 28; CG = 28	TG: multimodal exercise training program (aerobic exercises, strength, balance, and stretching)/ 2/w (60 min)CG: usual activities	12	No effects on mobility, executive function in AD patients but significant in MCI patients
Enette 2020¹⁹	Changes in BDNF	Aerobic fitness, cognitive performance and quality of live	Mild to moderate AD/77.9 ± 7.6/44%	Mild to moderate AD/77.9 ± 7.6/44%	3; Continues TG-C = 16; Interval TG-I = 17; CG = 21	TG-C and TG-I: cycling 2/w (30 min)CG: usual activities	9	No significant difference between the two training groups in the BDNF levels
Frederiksen 2018²⁰	Hippocampal atrophy	Cognitive functions, daily living	Mild to moderate AD/67.8 ± 7.7/65%	Mild to moderate AD/69.8 ± 7.7/60%	2; TG = 36; CG = 35	TG: moderate-to-high-intensity aerobic exercise 3/w60 min)CG: usual care	16	No significant differences in regional cortical thickness
Frederiksen 2019²¹	Cortical Aβ		Mild to moderate AD/n.s./n.s.	Mild to moderate AD/n.s./n.s.	2; TG = 20; CG = 16	TG: moderate-to high-intensity aerobic exercise/3/w (60 min)CG: usual care	16	No effect of the exercise intervention on cortical Aβ compared with usual care
Frederiksen 2023²²	Neurofilament light levels (NfL)		Mild AD/69.5 ± 7.8/54%	Mild AD/70.6 ± 7.2/58%	2; TG = 107; CG = 93	TG: moderate- to high-intensity aerobic exercise/3/w(60 min)	17	There was no effect of the intervention on serum NfL
Fonte 2019²³	Cognitive function	attention, memory, executive functions, behavioral disorders	AD TG1/79 ± 9/36.8%; AD TG2/79 ± 9/30%	AD/80 ± 7/38%	3; TG-C = 19; TG-P = 20 CG = 21	TG-C = cognitive training; TG-P = physical training; 90 min/day, three days/w	24	TG-C and TG-P preserved the cognitive status
Jensen 2019²⁴	Neuroinflammatory markers (8-isoprostane, sTREM2, IFNγ, IL10, IL12p70, IL13, IL1β, IL2, IL4, IL6, IL8, and TNFα.		Mild AD/69/55%	Mild AD/71/72%	2; CG = 92; TG = 106	TG: aerobic physical exercise (treadmill, stationary bike, cross trainer/3/w(60 min)	16	Most inflammatory markers remained unchanged after exercise, except for the increase of sTREM2
Jensen 2020²⁵	Effect of physical exercise on the lipid profile, insulin and glucose	Effect of APOE genotype on cholesterol metabolism in plasma	Mild AD/69.9/50%	Mild AD/71.3/60%	2; TG = 107; CG = 93	TG: Moderate-to-high intensity exercise program/3/w(60 min)	16	No significant differences were found for the levels of total cholesterol, LDL-C, HDL-C, TG, glucose, and insulin at baseline between the groups, but a significant increase in plasma HDL-C levels between the TG compared to CG. No differences between APOE ε4 carrier and noncarriers
Lam 2022²⁶	Cognitive function	Episodic and working memory, attention, language, executive function and quality of life	Mild AD/80.3 ± 6.2/17%	Mild AD/80.8 ± 6.3/23%	4; TG-WM =94; TG-PE = 94; TG WM + PE = 94; CG = 94	TG-WM: Working memory training/2/w(20 min). TG-PE: Physical exercise/ 2/w (20 min + 20 min). TG-WM + PE TG: Physical exercise/2/w (20 min + 5 min rest + working memory)	6	TG-WM, TG-PE and TG-WM + PE demonstrated improvements in memory and verbal fluency but not in cognition outcomes
Lanza 2018²⁷	Cognitive function	Functional independence, depressive symptoms and functional status	Mild to moderate AD/77 ± 8/0%	Mild to moderate AD/88 ± 7/16. 7%	2; TG = 6; CG = 6	TG: 3 times/w (2 sessions aerobic exercises (75 min each) + 1 shiatsu (40 min); CG: 3 sessions of aerobic exercise/w	4	Within groups comparison showed improvement on cognitive, functional activities and depression. Intergroup show differences in functional activities and depression
Lok 2023²⁸	Cognitive function	Depression	AD/72.80 ± 3.99/50%	AD/73.88 ± 4.85/47.2%	2; TG = 36; CG = 36	TG: musical exercise 3/w(30 min) + walking 2/w(40 min); CG: not in the physical program	12	Cognitive functions scores improved, and depression decreases in patients participating in the physical program.
Menengiç 2021²⁹	Cognitive function and functional mobility	Daily living activities, Functional independence, depression and anxiety	Mild to moderate AD/77.7 ± 5.29/30%	Mild to moderate AD/80.6 ± 6.11/30%	2; TG = 10; CG = 10	TG: online real-time motor-cognitive dual-task exercise treatment/5/w(15 min); CG: daily routine	6	TR provides a significant change in cognition and mobility, improve functional independence, and reduce anxiety and depressive symptoms
Min 2021³⁰	Cognitive function	Balance function, gait and blood Aβ	AD/78.4 ± 8.5/25%	AD/79.6 ± 7.5/16.67%	2; TG =16; CG = 18	TG: aerobic, balance, and muscle strengthening exercises + cognitive training (numbers, words, and pictures); CG: exercise training	8	Dual-task versus single-task improved cognitive and bodily functioning and reduced β-amyloid levels
Musaeus 2022³¹	Functional brain connectivity		Mild to moderate AD/n.s./n.s.	Mild to moderate AD/n.s./n.s.	2; TG = 24; CG = 21	TG: moderate-to-high-intensity aerobic exercise/3/w (60 min)	16	Any exercise-induced changes in functional resting-state connectivity from baseline to follow-up were detected
Nagy 2021³²	Cognitive function and quality-of-life	Hemoglobin and anthropometric measurements	Mild anemic AD/69.50 (72.00–68.00)/50%	Mild anemic AD 70.00 (67.00–72.00)/50%	2; TG = 30; CG = 30	TG: aerobic exercise 3 days/w for 45–60 min per session + nasal laser irradiation and wrist laser acupuncture via a laser watch; CG: exercise + laser placebo	12	Both groups showed improved cognitive functions and hemoglobin levels, the increment was higher in the TG
Orcioli-Silva 2018³³	Kinematic parameters of gait		AD/n.s./n.s.	AD/n.s./n.s.	3; TG = 15; CG = 15; HG = 15	TG: physical activity/ 3/w(60 min)	16	HG presented greater stride length and stride velocity compared to the CG, while there were no differences between the TG and CG in the countdown and gait parameters
Papatsimpas 2023³⁴	Cognitive function	Daily living activities	Mild AD/TG-AR 76.82 ± 5.73/36.8%; TG-R 76.07 ± 5.7/17%	Mild AD/78.75 ± 7.06/12.3%	3; TG-A = 57, TG-B = 57; CG = 57	TG-AR: Aerobic exercise at home moderate intensity 5/w(30 min) + resistance exercise 3/w(40–45 min); TG-R: resistance exercise 3/w(40–45 min); CG: usual daily activity	12	Both aerobic and resistance exercise programs had a significant positive effect on cognitive function and instrumental activities of daily living
Parvin 2020³⁵	Cognitive function	Depression, anthropometric index (height, body mass, BMI, body fat), physical performance, functional abilities, brain oscillation	Mild AD/67.4 ± 8.8	Mild AD/67.4 ± 8.8	2; TG = 13; CG = 13	TG: (40–60 min of exercise training and simple brain activities (eyes-closed training and cognitive activities)) 2/w; CG: n.s.	12	Significant improvements in cognitive function, working memory, attention, executive function, and depression
Pedrinolla 2020³⁶	Vascular function and physical function		AD/79 ± 8/n.s.	AD/79 ± 8/n.s.	2; TG = 20; CG = 19	TG: moderate– high-intensity aerobic and strength training/3/w(90 min);CG: included cognitive stimuli (visual, verbal, auditive)	24	TG showed improvements in peripheral vascular function
Perttila 2018³⁷	Cognitive function, physical functioning and mobility		AD/78/62%	AD/78/60%	2; TG = 129; CG = 65	TG: home-based or group-based exercise/2/wCG: normal care	48	Exercise reduced the risk of falls among both nonusers and users of drugs with anticholinergic properties
Roitto 2018³⁸	Daily falls		AD/65/63%	AD/65/34%	2; TG = 120; CG = 59	TG: group-based exercise/(60 min)CG: usual care	48	The incidence of falls increased linearly in the CG but not in the TG
Salisbury 2022³⁹	Cardiorespiratory fitness	Dose-response	Mild to moderate AD/77.0 ± 6.6/60%	Mild to moderate AD/78.9 ± 5.6/56%	2; TG = 53; CG = 25	TG: cycling/3/w(30–60 min)CG: stretching/3/w(30–60 min)	24	Cardiorespiratory fitness improved. Establish exercise dose is essential to obtain results
Shaw 2021⁴⁰	Cognitive function	Daily living activitiesQuality of life	Mild to moderate AD/78.5 ± 6.69/n.s	Mild to moderate AD/82.21 ± 6.62/n.s	2; TG = 20; CG = 20	TG: 3/w(45 min)CG: no exercise	8	TG showed improvements in cognitive function and maintained daily living functions
Sobol 2018⁴¹	Cardiorespiratory fitness	Cognitive functionNeuropsychiatric symptoms	AD/n.s./n.s.	AD/n.s./n.s.	2; TG = 29; CG = 26	TG: strength and moderate-to-high intensity aerobic exercise 3/w(60 min)CG: no exercise	16	TG presented improvements in cardiorespiratory fitness associated with cognitive and neuropsychiatric symptoms
Todri 2019⁴²	Cognitive function, quality of life, depression, neuropsychiatric symptoms, autonomy and equilibrium		Mild to moderate AD/80.21 ± 5.4/33%	Mild to moderate AD/81.90 ± 4.8/38%	2; TG = 90; CG = 45	TG: GPR/2/w(30–40 min)CG: n.s.	24	Improvements in cognitive, depression, neuropsychiatric symptoms, physical performance, and quality of life
Todri 2020a⁴³	Cognitive function, quality of life, depression, neuropsychiatric symptoms, autonomy and equilibrium		Mild to moderate AD/81.87 ± 5.24/37.8%	Mild to moderate AD/80.47 ± 5.59/51.1%	2; TG = 45; CG = 45	TG: GPR/3/w(40 min)CG: nursing home activities	24	Improvements in cognition, mood, behavioral disorders, balance and quality of life
Todri 2020b⁴⁴	Cognitive function, quality of life, depression, neuropsychiatric symptoms, autonomy and equilibrium		Mild to moderate AD/80.2 ± 5.5/32%	Mild to moderate AD/81.4 ± 4.5/34%	2; TG = 90; CG = 70	TG: GPR/2/w(30–40 min)CG: n.s.	24	Improvements in cognition, psychological symptoms, and autonomy
van der Kleij 2018⁴⁵	Cerebral blood flow		Mild to moderate AD/68 ± 7/63%	Mild to moderate AD/69 ± 7/59%	2; TG = 71 ; CG = 71	TG: exercise/3/w(60 min)CG: care as usual	16	No effects on cerebral blood flow
Vidoni 2019⁴⁶	Functional independenceTotal caregiving time	Functional disability	Mild AD/n.s./n.s.	Mild AD/n.s./n.s.	2; TG = 33 ; CG = 32	TG: moderate exercise/ 3–5/w(60–150 min);CG: stretching and toning/3–5/w(60–150 min)	6	TG showed improvements in instrumental activities of daily living
Yang 2022⁴⁷	Global cognition	Verbal learning, executive functions, depression, daily life functions, functional connectivity, Aβ₄₀, Aβ₄₂, BDNF, IGF-1, TNF-α, IL-6 and sTREM2 levels in plasma	Mild AD/73.1 ± 5.2/20%	Mild AD/75.9 ± 8.0/22%	2; TG = 10; CG = 9	TG: sport stacking 5/w(30 min)CG: clinic routine management	12	Improvements in auditory verbal learning, BDNF levels, and brain regional function connections
Yu 2021⁴⁸	Global cognition	Episodic memory, executive function, attention, processing speed, and language	AD/77.4 ± 6.6/56%	AD/77.5 ± 7.1/53%	2; TG = 64; CG = 32	TG: cycling/3/w(20–50 min)CG; stretching 3/w(20–50 min)	24	No differences between TG and CG
Yu 2021⁴⁹	Hippocampal volume, temporal meta-regions of interest, cortical thickness, white matter hyperintensity volume, and network failure quotient	Cognition	AD/77.2 ± 6.3/58%	AD/77.4 ± 6.5/43%	2; TG = 38; CG = 21	TG: moderate-intensity cycling/3/w(20–50 min)CG: low-intensity stretching exercise/ 3/w(20–50 min)	48	Hippocampal volumes decreased in the TG
Yu 2021⁵⁰	Interindividual response to exercise	Cognition	Mild to moderate AD/77.0 ± 6.6/60%	Mild to moderate AD/78.9 ± 5.6/56%	2; TG = 53; CG = 25	TG: aerobic fitness/3/w (30–60 min)	24	Great interindividual cognitive-related responses to aerobic fitness in TG
Yu 2022⁵¹	Feasibility of recruitment, retention, and blood sample collection	Plasma Aβ₄₂ and Aβ₄₀ (Aβ_42/40) ratio, p-tau 181, and t-tau.	Mild to moderate AD/76.8 ± 7.6/61.1%	Mild to moderate AD/79.3 ± 5.55/75%	2; TG = 18; CG = 18	TG: cycling/3/w (20–50 min);CG: stretching movements and static stretches at low intensity/3/w(40–60 min)	24	No effects on p-tau181, t-tau and Aβ_42/40
Yun 2021⁵²	Muscle strength		Moderate AD/78.3 ± 5.3/n.s.	Moderate AD patients/78.2 ± 4.8/n.s.	2; TG = 13; CG = 13	TG: simple bedside exercise/5/w(30 min)CG: n.s.	12	Isometric maximal voluntary contraction for hip flexion and knee extension significantly increased in TG

AD: Alzheimer's disease; Aβ: amyloid-β; BDNF: brain derived neurotrophic factor; CEG: combined exercise group; CG: control group; EG: exercise group; GPR: global postural reeducation; HDL-C, high-density lipoprotein cholesterol; HG, healthy group; IFNγ: interferon gamma; IL, interleukin; LDL-C, low-density lipoprotein cholesterol; MCI: mild cognitive impairment; n.s.: not specified; NfL; neurofilament light chain; p-tau: phosphorylated tau; PE, physical exercise; sTREM2, soluble trigger receptor expressed on myeloid cells 2; t-tau: total tau; TG: treatment group; TNF-α: tumor necrosis factor alpha; W: week; WM: working memory.

Table 3.

Nutritional intervention studies.

Author/Year of publication	Primary Outcome/s	Secondary Outcome/s	Treatment group (TG)/Age/Sex (% men)	Control group (CG)/Age/Sex (% men)	Number of groups and sample size	Intervention and number of times administered	Duration of the intervention (weeks)	Results
Agahi 2018⁵³	Cognitive function	Serum inflammatory and oxidative biomarkers levels	AD/79.70 ± 1.7/28%	AD/80.57 ± 1.79/43%	2; TG = 30; CG = 30	6 probiotic strains in 2 different capsules. 1 capsule a day every other day	12	No effects on cognition, inflammatory and oxidative markers
Akhgarjand 2022⁵⁴	Cognitive function	Daily Living and anxiety	Mild to moderate AD/TG1: 67.93 ± 7.8/33.3%; TG2: 67.90 ± 7.9/33.3%	Mild to moderate AD/67.77 ± 7.9/33.3%	3; TG1 = 30; TG2 = 30; CG = 30	2 capsules/day: 1. L. rhamnosus HA (each capsule contained 10¹⁵ CFU probiotic); 2. B. longum R0175 (each capsule contained 10¹⁵ CFU probiotic); 3. Placebo (one capsule containing xylitol, maltodextrin, and malic acid)	12	Significant positive effect on cognition in both probiotics’ groups (orientation, registration, attention, recall, language, and visuospatial domains)
Brandt 2019⁵⁵	Memory score	Cognition and mood	Mild AD/73.8 ± 6.37/55%	Mild AD/69.09 ± 5.05/66%	2; TG = 14; CG = 13	Modified Atkins Diet and National Institute on Aging's recommendations for senior nutrition as control	12	Adherence: fair. The Modified Atkins Diet group had more energy and better daily functioning over time but no differences in cognitive functions. No particular effects on APOE ε4 carriers
Chen 2021⁵⁶	Cognitive function	Folate, vitamin B12, homocysteine and inflammatory biomarkers	AD/68.58 ± 7.29/26%	AD/68.02 ± 8.34/30%	2; TG = 51; CG = 50	TG: folic acid (1.2 mg/d) + vitamin B12 (50 μg/d); CG: starch tablets	24	Cognition scores increased in the TG and TNF-α, SAM and SAH decreased
Foroumandi 2023⁵⁷	Memory, depression, quality of life, blood pressure, and serum MDA, TAC levels and blood pressure		AD/72.05 ± 2.59/34.1%	AD/72.12 ± 1.98/34.1%	2; TG = 41; CG = 41	TG: 5 cc orally of fenugreek seed extract (equivalent to 500 mg of dry extract)	16	No differences in memory status, depression, but significant differences in blood pressure and oxidative markers
Jernerén 2019⁵⁸	Cognitive function	Global function	Moderate AD/71.5 (70.6–74.4)/55.4%	Moderate AD/72.9 (71.0–74.8)/55.4%	2; TG = 88; CG = 83	TG: 1720 mg of DHA and 600 mg of EPA + 16 mg vitamin E/d; CG: 4 g corn-oil including 2.4 g of linoleic acid + 16 mg vitamin E); second intervention TG and CG took omega-3 capsules	24	The effects of 3-FA supplementation on cognitive and clinical outcomes are related to baseline tHcy levels. No effect on cognition were detected
Jia 2019⁵⁹	Cognitive function	Aβ-related biomarkers, vitamin D	AD/68.02 ± 5.90/44.76%	AD/67.53 ± 5.15/42.9%	2; TG = 105; CG = 105	TG: 800 IU vitamin D3/d; CG: starch	48	Improvement in cognition parameters and Aβ-related biomarkers (Aβ₄₂, AβPP, BACE1, APPmRNA and BACE1mRNA)
Kainuma 2022⁶⁰	Cognitive function	Daily life activity, apathy and neuropsychiatric symptoms	Mild AD/75 ± 6.6/38.46%	Mild AD/76 ± 7.1/42.86%	2; TG = 39; CG = 35	TG: 2.5 g of hachimijiogan extract 3 times/day + AChEI; CG: AChEI	24	Significant improvements in cognitive function in women and people over 65 years
Li 2020⁶¹	Efficacy and safety of Hericium erinaceus mycelia capsules	Cognition, daily life activities, calcium, albumin, ApoE4, hemoglobin, BDNF, alpha1-antichymotrypsin and Aβ-peptide 1	Mild AD/74.30 ± 7.15/30%	Mild AD/77.05 ± 8.20/52.38%	2; TG = 20; CG = 21	TG: 350 mg/capsule containing 5 mg/g erinacine A/day; CG: placebo capsules	49	Cognitive scores improved in comparison to CG but not in pairwise comparison
Lin 2022⁶²	Cognitive function, daily activity function and proinflammatory cytokines		TG1 AD/78.95 ± 7.89/70.73%; TG2: AD/77.80 ± 8.49/67.5%; TG3: AD/76.73 ± 9.15/64.29%	AD/78.10 ± 8.59/62.5%	4; TG1 = 41; TG2 = 40; TG3 = 42; CG n = 40	TG1: DHA, 0.7 g/day; TG2: EPA, 1.6 g/day; TG3: EPA (0.8 g/day) + DHA (0.35 g/day); CG: soybean oil	96	No effect on cognitive, functional, and depressive symptoms or biomarkers, but spoken language ability and constructional praxis
Marianetti 2022⁶³	Cognition function, memory, visuospatial abilities, attention, language, executive functions, and behavioral disorders		Mild AD/67.0 ± 5.84/50%	Mild AD/67.8 ± 4.41/62.5%	2; Crossover CG-TG = 20; TG-CG = 20	TG: 2 capsules/d containing: 100 mg SAG + 160 mg oleuropein + 2 mg vitamin B6, 6 mcg vitamin B12 + 30 IU vitamin E + 8 mcg vitamin D3 + 6 mg piperine + 200 mg bacopa dry extract 200 mg; CG: no treatment	24	Reduction of cognitive deterioration and neuropsychiatric symptoms, improvement of memory, attention, language speech, attention and executive functions
Muangpaisan 2022⁶⁴	Cognitive function and neuropsychiatric symptoms	Blood: HNE. Efficacy and tolerability of mangostream extract	Mild to moderate AD/TG1: 77.2 ± 7.3/22.58%; TG2: 78.0 ± 5.5/32.25%	Mild to moderate 78.0 ± 6.2/37.5%	3: TG1 = 31; TG2 = 31; CG = 40	TG1: low dose 1 pill/d (280 mg); TG2: 1 pill/d first 12 w + 2 pills/d next 12 w; CG = placebo capsules	24	Significant improvements in cognitive functions with the high dose
Nolan 2022⁶⁵	Cognitive function	Skin carotenoid concentrations; serum carotenoid and vitamin E concentrations, plasma omega-3 fatty acid concentrations; dementia severity rating scale score, clinical collateral, quality of life and frailty	Mild to moderate AD/78.63 ± 7.21/34.2%	Mild to moderate AD/79.74 ± 5.30/42.1%	2; TG = 38; CG = 19	TG: carotenoids (10 mg lutein, 10 mg meso-zeaxanthin, 2 mg, zeaxanthin), omega-3 fatty acids (1 g, of which 500 mg DHA and 150 mg EPA), and vitamin E (15 mg D-α-tocopherol); CG: sunflower oil	48	A trend to improve cognitive decline and significant increments in blood nutrients and blood and skin carotenoids
Ota 2019⁶⁶	Cognitive function	Blood ketone levels (acetoacetate and β-hydroxybutyrate)	Mild to moderate AD/73.4 ± 6.0/55%	Mild to moderate AD/73.4 ± 6.0/55%	2; TG-CG = 10; CG-TG = 10 crossover design	TG: single administration of a ketogenic formula (20 g of medium chain triglycerides/35. 5 g total fat); CG = isocaloric formula with long chain triglycerides	n.s.	Increases of both the plasma acetoacetate and β-hydroxybutyrate but not effect on cognition
Phillips 2021⁶⁷	Cognitive function, daily functions and quality of life	Cardiovascular biomarkers (weight, body mass index, and blood markers: HbA1C, Triglycerides, HDL, LDL, Total cholesterol)	TG/CG: AD/68.0 ± 5.4/77%	CG/TG: AD/71.7 ± 6.2/46%	2; Crossover CG-TG =13; TG-CG = 13	TG: 58% fat (26% saturated, 32% no saturated), 29% protein, 7% fiber, and 6% net carbohydrate by weight; CG: 11% fat (3% saturated, 8% no saturated), 19% protein, 8% fiber, and 62% net carbohydrate by weight	12	Improvements in daily function and quality of life, not in cognition
Sanchez-Romero 2020⁶⁸	Oxidative stress markers (lipoperoxides, nitric oxide catabolites levels, oxidized/reduced glutathione ratio, and membrane fluidity]) and fatty acid profile in erythrocytes		AD/70.6 ± 12.1/10%	AD/73.3 ± 13.5/20%	2; TG = 10; CG = 10	TG1: Fish oil (0.45 g EPA and 1 g DHA); CG: pharmaceutical gel containing water, gelatin, gum, and sugar	48	Increases in plasma stearic acid, behenic acid, EPA, DHA and decrease in arachidonic and oxidative-stress markers
Tamtaji 2019⁶⁹	Cognitive function	Biomarkers of inflammation (CRP), oxidative stress (MDA, TAC, GSH, NO) and metabolic profile (glucose, lipid profile, insulin, HOMA-IR, QUICKI)	AD/n.s./n.s.	AD/n.s./n.s.	3; TG1 = 30; TG2 = 30; CG = 30	TG1: 200 mg/day selenium + probiotic (Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium longum (2 × 10^9 CFU/day each)); TG2: 200 mg/day selenium; CG: placebo	12	Improved cognitive function and some metabolic-inflammation markers (hs-CRP, TAC, GSH, markers of insulin and lipid metabolism)
Tofiq 2021⁷⁰	Biomarkers in CSF: Aβ₃₈, Aβ₄₀, Aβ₄₂, t-tau, p-tau, NfL) YKL-40, AChE, BuChE, sIL1RII, and IL-6	Correlation with cognitive function	AD/72 ± 8/56%	AD/68 ± 7/60%	2; TG = 20; CG = 20	TG: 2.3 g of omega-3 FA (0.43 g DHA and 0.15 g EPA); CG =��4 g of corn oil (0.6 g linoleic acid)	24	Significant effect on NfL and YKL-40. No correlation with cognition,
Torres-Mendoza 2022⁷¹	Oxidative stress biomarkers: hydroperoxides and enzymatic activities of catalase and superoxide dismutase		AD/n.s.	AD/n.s.	2; TG = 10; CG = 10	TG1: Fish oil (0.45 g EPA and 1 g DHA); CG: identical gel	48	Decrease in oxidative stress markers (carbonyl groups and hydroperoxides) and catalase activity
Vakilian 2021⁷²	Cognitive function, psychotic symptoms and pain		TG1: 81.52 ± 6.96/37.5%; TG2: 81.20 ± 7.20/40%	CG1: AD/79.54 ± 7.35/63.63%; CG2: 78.56 ± 7.90/30%	4; CG1 = 20; TG1 = 20; CG2 = 20; TG2 n = 20	CG1: risperidone (increasing dose 0.5 mg/1 mg/2 mg/); TG1: risperidone (increasing dose 0.5 mg/1 mg/2 mg/) and vitamin B12 (1 mg injected/month); CG2: quetiapine (increasing dose 12.5 mg/25 mg/50 mg/); TG2: quetiapine (increasing dose 12.5 mg/25 mg/50 mg/) and vitamin B12 (1 mg injected/month)	n.s.	Quetiapine showed better results (cognition, psychiatric symptoms, and pain) than risperidone and its effects were potentiated by B12 administration
Wang 2018⁷³	Cognitive function	Quality of life, and neuropsychiatric symptoms	Mild to moderate AD/76.3 ± 6.8/33.3%	Mild to moderate AD/74.6 ± 7.0/33.3%	2; TG = 21; CG = 21	TG: 4 capsules of 1000 mg each time (250 mg/capsule), 3 times daily, and 7 days weekly; CG: placebo, the same dose, size, color and flavor	6	No effect on cognition, quality of live or neuropsychiatric symptoms
Wang 2020⁷⁴	Cognitive function	Daily Living activities and serum levels of ACh, Aβ₄₂ and tau protein	Mild to moderate AD/65.48 ± 7.33/14.81%	Mild to moderate AD/60.88 ± 8.93/16.67%	2; TG = 27; CG = 24	TG: 5 g of JYF twice a day + 5 mg of donepezil-placebo once a day; CG: 5 mg of donepezil once a day + 5 g of a JYF-placebo twice a day	24	JYF effects were similar to donepezil in cognition, and serum biomarkers. No effects on daily living activities
Xu 2020⁷⁵	Cognitive function	Daily living activities and changes in plasma metabolites (Aβ₄₀, Aβ₄₂, Tau)	Mild to moderate AD/76.4 ± 3.2/36%	CG-TG: Mild to moderate AD/73.7 (69.6–77.8)/37.5%	2; Crossover CG-TG =13; TG-CG = 13	TG: medium chain triglycerides jelly 3 times/d (total dose of 17.3 g); CG: 19 g canola oil/d	4	Positive effects on cognitive abilities that may be related to the metabolism of LysoPC, oleic acid, linoleic acid, and palmitic acid, in addition to the ketogenic effect
Yulug 2023⁷⁶	Cognitive function and daily living activity	Safety and tolerability of combined metabolic activators	Mild to moderate AD/70.77 ± 8/53%	Mild to moderate AD/70.91 ± 7.54/50%	2; TG = 47; CG = 22	TG: 12.35 g L-serine, 1 g nicotinamide riboside, 2.55 g N-acetyl-L-cysteine, and 3.73 g L-carnitine tartrate. 0–4 w: 1 dose/day 5–12 w: 2 doses/day	12	Cognitive improvements, alterations in the hippocampal volumes and cortical thickness, plasma levels of proteins and metabolites associated with NAD + and GSH metabolism

ACh: acetylcholine; AChE: acetylcholinesterase; AChEI: acetylcholinesterase inhibitor; AD: Alzheimer's disease; Aβ: amyloid-β; AβPP: amyloid-β protein precursor; BACE1: β-secretase 1; BDNF: brain derived neurotrophic factor; BuChE: butyrylcholinesterase; CG: control group; CRP: c-reactive protein; CSF: cerebrospinal fluid; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; FA: fatty acids; GSH: glutathione; HbA1C: hemoglobin A1c; HDL: high-density lipoprotein; HNE, 4-hydroxynonenal; HOMA-IR: Homeostasis model assessment for insulin resistance; hs-CRP: high sensitivity c-reactive protein; IL: interleukin; JYF: Jiannao Yizhi formula; LDL: low-density lipoprotein; LysoPC: 1-Lysophosphatidylcholine; MDA, malondialdehyde; n.s.: not specified; NAD+: nicotinamide adenine dinucleotide; NfL; neurofilament light chain; NO, nitric oxide; p-tau: phosphorylated tau; QUICKI: quantitative insulin-sensitivity check index; SAG: S-acetyl glutathione; SAH: S-adenosylhomocysteine; SAM: S-adenosyl-L-methionine; sIL1RII: soluble IL-1 receptor type II; t-tau: total tau; TAC, total antioxidant capacity; TG: treatment group; tHcy: total homocysteine; TNF-α: tumor necrosis factor alpha; w: week; YKL-40: chitinase-3-like protein 1.

Table 4.

Studies related to cognitive training.

Author/Year of publication	Primary Outcome/s	Secondary Outcome/s	Treatment group (TG)/Age/Sex (% men)	Control group (CG)/Age/Sex (% men)	Number of groups and sample size	Intervention and number of times administered	Duration of the intervention (weeks)	Results
Benitez-Lugo 2023⁷⁷	physical-cognitive tasks, memory, attention, balance, gait, and risk of falling		AD/n.s./14.3%	AD/n.s./37.5%	2; TG = 7; CG = 8	TG: Nintendo Wii games (“Penguin Slide” game for training balance and “Step Plus” game for training balance and aerobic exercises) 2/w (30 min); CG = habitual activity (independent sessions of mobility exercises and cognitive stimulation in their Alzheimer's association)	8	Memory, balance, gait, and risk of falling improved
Georgopoulou 2023⁷⁸	Cognitive function and language deficits	to evaluate the prospect of the cognitive benefits been transferred to everyday functioning capacity	AD/75.00 ± 5.21/30%	AD/75.20 ± 4.73/30%	2; TG = 10: CG = 10	TG: computer training of cognitive domains 2/w(60 min); pencil-paper training of cognitive domains 2/w(60 min)	15	Both programs had positive effects but in different cognitive and language domains, only pencil impact on patients’ daily lives
Jung 2023⁷⁹	Cognitive function, mood, and activities of daily living		Mild to moderate AD/77.4 ± 8.4/33.3%	Mild to moderate AD/75.4 ± 8.4/33.3%	2; TG = 21 (divided in 2 for crossover intervention); CG = 21	TG: cognitive training 2/w for 4w + music, and art therapies via internet + same in-person therapy 2/w for 4w (crossover intervention)CG: only pharmacological treatment	8	Positive effect on the cognitive function, depression, anxiety, and ADL. The internet-based intervention was found as effective as in-person intervention
López 2022⁸⁰	Neuropsychological assessment (global cognitive function, attention, memory, praxis, language, executive functions and intelligence)		Mild to moderate AD/83.30 ± 3.71/20%	Mild to moderate AD/80.50 ± 6.72/30%	2; TG = 10; CG = 10	TG: cognitive activities/3/w(60 min); CG: routine care	24	Intervention maintained the cognitive performance of patients, while the control group showed a deterioration.
Nousia 2018⁸¹	Evaluation of cognitive performance (memory, delayed memory, word recognition, attention, executive function, processing speed, semantic fluency, and naming)	Daily activities and depression	Mild AD/76.24 ± 5.14/36%	Mild AD/76.32 ± 5.38/20%	2; TG = 10; CG = 7	TG: computed-based cognitive training semiweekly (60 min); CG: standard clinical care	15	Beneficial impact on linguistics and cognitive performance
Oliveira 2021⁸²	Executive functioning	Global cognition, functionality, depression, and dementia rating	AD/82.60 ± 5.42/30%	AD/84.14 ± 6.30/28.6%	2; TG = 10; CG = 7	TG: cognitive stimulation with non-immersive virtual reality 2/w(45 min); CG: usual care	12	Improvements in global cognition but no in executive functions
Trebbastoni 2018⁸³	Cognitive function (memory, attention, language, visuo-spatial functions, frontal functions and praxis)		Mild to moderate AD/74.26 ± 6.97/52%	Mild to moderate AD/76.01 ± 6.46/40%	2; TG = 54; CG = 86	TG: Cognitive treatment 2/w(75 min) CG: usual care	24	Significant improvement in MMSE (6 months) that disappears at 12 months
Wang 2022⁸⁴	Cognitive function (episodic memory, executive function, working memory, attention processing, verbal ability, and inferring capability)	Evaluation of daily living activities	Mild AD/63.24 ± 2.62/53.33%	Mild AD/62.75 ± 2.64/63.33%	2; TG = 30; CG = 30	TG: 4 d/w of 1 h of cognitive training (episodic memory, executive function, working memory, attention processing, verbal ability, and inferring capability); CG: conventional nursing	20	Improvement in cognitive abilities and daily activities performance

AD: Alzheimer's disease; CG: control group; MMSE: Mini-Mental State Examination; n.s.: not specified; TG: treatment group; w: week.

Table 5.

Other related with other lifestyle interventions studies.

Author/Year of publication	Primary Outcome/s	Secondary Outcome/s	Treatment group (TG)/Age/Sex (% men)	Control group (CG)/Age/Sex (% men)	Number of groups and sample size	Intervention and number of times administered	Duration of the intervention (weeks)	Results
Chen 2022⁸⁵	Determination of oral health	Cognitive and behavioral changes, psychological adjustment, activities of daily living and oral microbiome	AD/82.70 ± 6.03/30.3%	AD/83.00 ± 6.04/27.3%	2; TG = 33; CG = 33	Oral health intervention strategies, including structured visits (3/w), oral self-care (3/w), and self-management training 1/w(45 min)	24	Improvement in oral health in the TG was accompanied of improvements in cognition and daily functioning and decrease in neuropsychiatric symptoms
Giulietti 2023⁸⁶	Cognitive function, quality of life and depression		Mild AD/82.8 ± 5.6/36.4%	Mild AD/82.9 ± 4.2/22.7%	2; TG = 22; CG = 22	TG: relaxation training with Jacobson technique 3/w(90 s) 1 month + 5 mindfulness-based interventions 3/w(15–20 min) + relaxation 5 months; CG = no treatment	24	Mindfulness training is effective in increasing quality of life and preventing worsening in patients with early-stage AD
Harrison 2021⁸⁷	Cognitive function, verbal and physical agitation		AD or related dementia/79.7 ± 11.2/28.4%	AD or related dementia/80.6 ± 12.6/38%	2; TG = 103; CG = 55	TG: music (TG); CG: audiobooks/n.s.	8	Decreases in agitation were attributable to both music and audiobooks in 3 of 4 agitation subscales
Kim 2021⁸⁸	Sleep quality, cognition, mood, behavioral and neuropsychiatric symptoms and caregiver burden		Mild to moderate AD/77.36 ± 5.79/14.3%	Mild to moderate AD/78.55 ± 7.71/45.4%	2; TG =14; CG =11	TG: blue-enriched white light 1/day(60 min); CG = wear blue-attenuating sunglasses	2	Blue light intervention could affect subjective and objective sleep and cognitive performance
Kim 2021⁸⁹	Cognitive function (assesses attention, language, visuospatial function, memory, and frontal-executive function) and noncognitive symptoms (sleep quality, depression, anxiety and stress).	Effects of muscle relaxation on cortical thickness and default mode network, changes using structural MRI and resting-state functional MRI.	MCI and mild AD/69.4 ± 7.3/26.9%	MCI and mild AD/72.5 ± 8.4/34.5%	2; TG = 25; CG = 25	TG: full body massage with EAM chairs, n.s.; CG = routine care	48	Improvements in working memory and sleep quality
Lin 2022⁹⁰	Electrochemical signals	Cognitive function, sleep, anxiety, and depression	Mild AD/80.0 ± 6.9/25%	Mild AD/77.3 ± 9.6/28.57%	2; TG =11; CG = 11	TG: grounding 5/w(30 min); CG: sham grounding wire was used	12	Significant improvement in sleep quality but not in anxiety or depression
Liu 2021⁹¹	Anxiety severity, level of depression and musical aptitude		AD/86.6 ± 4.5/100%	AD/86.9 ± 5.7/100%	2; TG =25; CG = 25	TG: 60-min group music session with percussion instruments once per week; CG: rest and reading sessions at the same intervals and under the same conditions	12	Group music percussion intervention significantly reduced the anxiety scores, in patients with high musical aptitude reduction was higher
Quintana-Hernández 2023⁹²	Neuropsychological assessment (behavioral and psychological symptoms of dementia)		AD/n.s.	AD/n.s.	4; TG1 = 5; TG2 = 5; TG3 = 5; TG4 = 5; CG = 5	TG1: mindfulness; TG2: cognitive stimulation; TG3: progressive muscle relaxation; CG: usual care	96	Mindfulness improved depressive symptomatology, prevented anxiety and slowed cognitive decline
Quintavalla 2021⁹³	Wellness and Cognitive function		Medium severe AD/n.s./n.s.	Medium severe AD/n.s./n.s.	2; TG = 30; CG = 30	TG: animal therapy session 2/w(30 min); CG: usual activities	12	Benefits in global cognition, wellbeing, personal satisfaction, coping strategies, and emotional skills

AD: Alzheimer's disease; CG: control group; EAM: electrical automatic massage; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; n.s.: not specified; TG: treatment group; w: week.

Exercise interventions

Exercise emerges as the most frequently utilized intervention for AD patients, comprising a total of 40 RCTs out of 81 studies (Table 2). More than 50% of the studies used moderate- to high-intensity aerobic exercise, while the rest focused on low-intensity exercise or postural reeducation/stretching exercise. These aerobic exercise programs typically involved activities such as cycling, treadmill walking, and aerobic exercises. Aerobic exercise has been shown to have various benefits for individuals with AD, including improvements in mobility, functional activities and reducing the risk of falls,^{29,33–35,37,38,40,46} which may indicate a positive impact on neurodegenerative processes. The effects of aerobic exercise on cognitive function are less evident, as certain studies report enhancements in cognitive functions^13,28,29,40 while others did not detect any discernible effect.^26,48 Most studies employing aerobic exercise to investigate its effects on inflammation markers or disease development fail to demonstrate significant results. No effects of exercise were detected on brain-derived neurotrophic factor (BDNF) levels,¹⁹ cortical thickness,²⁰ cortical amyloid-β (Aβ),²¹ serum neurofilament light chain (NfL) levels,²² cerebral blood flow,⁴⁵ p-tau181, t-tau and Aβ_42/40⁵¹ or the inflammatory markers 8-isoprostane, interferon gamma (IFNγ), Interleukin-10 (IL10), IL12p70, IL13, IL1β, IL2, IL4, IL6, IL8, and tumor necrosis factor alpha (TNFα).²⁴ However, in another study the combination of exercise with cognitive training showed an effect on Aβ levels.³⁰ Other studies employ multimodal exercises, combining aerobic exercise with strength, balance, and stretching components.^{15,17,18,42,51} Two of these studies find benefits in functioning, strength, and balance,^15,17 while the other studies only find benefits when multimodal exercise is applied to individuals with mild cognitive impairment but not in AD patients¹⁸ or did not find effect on plasma biomarkers of AD patients.⁵¹ The other type of studies primarily focus on global postural reeducation showing effects on cognition, psychological symptoms, physical activity, and quality of life,^42–44 sport stacking (a sport that involves stacking of specially designed cups),⁴⁷ bed exercises⁵² and a study on hand exercises to enhance feeding efficiency.¹⁶ Of particular interest are studies in which exercise is combined with another intervention to observe synergistic effects. This is the case with the combination of exercise with working memory training,²⁶ cognitive training,^30,33 photobiomodulation,³² and visual stimulation.³⁵ The sample sizes in these exercise-related studies varied. Some studies had smaller sample sizes, such as 10 or less participants in each group,^13,27,29,47 while others had larger sample sizes with a participant number close to 100 individuals per group,^{22,24,26,37,38,42} with a common range falling between 20 to 30 participants in each group. Regarding the duration of the exercise intervention, the shortest exercise intervention used in these studies is 4 weeks, the longest is 96 weeks, and the average is between 12–16 weeks.

Supplements and diets

In a total of 24 studies, the treatment approach focused on dietary intervention (Table 3). Omega-3 fatty acid supplementation emerged as the most commonly utilized treatment in nutritional intervention studies, with intervention periods ranging from 24 to 96 weeks. While this supplementation appears to reduce oxidative stress markers, none of the studies demonstrated cognitive improvement in patients, despite limited sample sizes, as only two studies included more than 50 patients per group.^58,59 Vitamins, whether used individually or in combination with other vitamins or compounds, are also among the most utilized supplements. For instance, vitamin D supplementation⁵⁹ and folic acid combined with vitamin B₁₂⁵⁶ have been demonstrated to improve cognition and related markers, or to enhance the effects of pharmaceuticals.⁷²

Regarding diets, one study investigates the feasibility of implementing the Atkins diet and its effects on cognitive function,⁵⁵ while two studies explore the use of the ketogenic diet or a ketogenic formula.^66,67 None of these studies demonstrate a positive effect on cognitive function, although they do show an impact on other parameters related to daily function such as attention and language (Table 3). Additionally, two studies utilize probiotics as a dietary intervention^53,54 and one examines co-supplementation of probiotics with selenium yielding varying results on cognition.⁶⁹ Two studies report positive outcomes^54,69 while the third shows no effect.⁵³ Notably, all three studies have the same duration and sample size but employ distinct probiotic strains (Table 3), with none of them evaluating the potential alteration in gut microbiota as an outcome.

Cognitive training

Cognitive training emerges as a particularly effective therapeutic approach for enhancing the cognitive functions of AD patients. Moreover, the research covered in this review highlights significant success in utilizing emerging technologies like virtual reality⁸² and computer-based activities^78,84 for this purpose (Table 4). However, it is important to acknowledge a limitation regarding the relatively small sample sizes used in several of these studies. Out of the 8 studies examined, 5 of them feature sample sizes equal to or less than 10, with only one study having a subject pool exceeding 50 per group. Additionally, the interventions vary in duration, ranging from 8 to 24 weeks.

Other related lifestyle interventions

This section encompasses studies employing highly diverse practices that can be integrated into the patient's lifestyle, including mindfulness,⁸⁶ electric massage,⁸⁹ grounding,⁹⁰ music listening,⁹¹ dog companionship,⁹³ additional blue light exposure,⁸⁸ and oral health⁸⁵ (Table 5). Many of these studies involved small populations and short-term interventions, which limits the robustness of the conclusions. However, most studies observed improvements in AD patients across various parameters, such as daily functioning, cognition, and a reduction in neurological symptoms (Table 5).

Risk of bias

To assess the quality of the RCTs included in this systematic review, we utilized the modified Jadad quality scale, previously validated for evaluating the quality of AD drug reports.¹¹ The risk of bias was rated by two independent researchers (SCV and MT), the interrater agreement kappa coefficient (κ) was calculated obtaining an overall value of 0.94 indicating strong agreement between the two raters. The mean Jadad scale score for all the studies included in this review was 5.58 ± 1.72, indicating that most studies met quality standards. Only 12 out of 80 studies did not achieve a score of 4 on the Jadad scale, while 25 out of 80 obtained a score ≥7 (Supplemental Tables 1–4). Regarding the different interventions considered in this review, dietary interventions received the highest Jadad scale scores (6.52 ± 1.63) (Supplemental Table 2), while other lifestyle-related interventions scored the lowest (5.22 ± 2.24), with physical exercise interventions similarly scoring (5.22 ± 1.59) (Supplemental Table 4). RCTs focusing on cognitive training had a mean Jadad scale score of 5.63 ± 1.75 (Supplemental Table 3).

Discussion

After conducting a thorough analysis of RCTs, our systematic review suggests that lifestyle interventions are associated with moderate improvements in the quality of life for individuals affected by AD. However, overall, these interventions do not lead to significant changes in cognitive function. Among various interventions, evidence from medium-term studies suggests that exercise programs are linked to a modest enhancement in quality of life aspects, such as mobility, balance, and fall incidence, irrespective of the type or intensity of training.^{15,17,29,37,38,42,44}

However, the conclusions drawn from other studies included in our systematic review regarding the exercise effects on cognitive function are inconclusive due to limitations such as a small number of patients in the sample size or the short duration of the intervention, with some interventions lasting as briefly as 4 to 6 weeks. Unraveling the specific contribution of particular types of exercise to AD prevention poses a significant challenge. The significant variability in individual responses to exercise within the population^39,48 and the different tools employed in assessing exercise stand as noteworthy concerns. To mitigate these uncertainties, future studies incorporating objective measures of exercise may provide more accurate data and help address the current ambiguities surrounding this topic. The biological mechanisms underlying the impact of exercise on AD patients are diverse, with some yet to be fully elucidated. Exercise has been found to enhance immunity, with certain studies demonstrating improvements in natural killer cell activity.^94,95 Additionally, exercise has been shown to improve microcirculation, thereby reducing hypoxic environments, which are significant for AD development.⁹⁶

Regarding nutritional interventions, none of the analyzed studies demonstrated any difference in cognitive function or daily parameters in participants who consumed omega-3 fatty acid or fish oil supplementation compared to those who did not.^{58,62,65,68,70} While omega-3 fatty acids could potentially have a protective effect against AD due to their anti-inflammatory and neuroprotective properties,⁹⁷ there are currently no intervention studies in humans with clear and consistent results. Supplementation with different vitamins (D, B₁₂, folic acid, etc.), as well as various types of plant extracts, appears to improve the cognitive abilities of AD patients,^56,59,63,64 possibly by reducing the oxidative stress associated with this disease. However, more studies with large sample sizes and adequate characterization of the extracts are needed to obtain clear results. Much of the previous support for a positive association between healthy diets, such as the Mediterranean diet, and healthier AD patients has come from observational studies. These diets combine numerous components (omega-3, polyphenols, fiber, etc.) with a potential effect on AD and also reflect a healthier lifestyle in those who consume them. There are other hypotheses that could account for the observed results, in addition to the reduction in oxidative stress or neuroinflammation, which have not been investigated in the studies. For example, changes in body composition, such as obesity, are related to the incidence of AD,⁹⁸ increasing the production of proinflammatory factors and some hormones that can promote AD,⁹⁹ or changes in the intestinal microbiota that can be exerted by diet or exercise.^100,101

Furthermore, cognitive training involving daily activities and other lifestyle interventions, such as music, light exposure, or mindfulness, have been identified in this review as potential interventional factors that may enhance cognitive function and reduce overall deterioration. However, it is important to note that these studies have several limitations that should be considered. Most studies included in our review were conducted with a very limited number of patients, and much of the data were collected based on participants’ self-reports, making it difficult to establish the actual intensity or duration of the activities performed. Additionally, the biological mechanisms underlying these parameters have not been thoroughly investigated, with only correlational studies conducted thus far.

Probably multi-component lifestyle interventions are more effective in achieving significant health improvements compared to single-component interventions; however, only a few studies of this review use more than one approach. Our study highlights the lack of high quality randomized controlled trials including different lifestyle intervention to sustain their synergistic effects on AD patients. Just recently, Ornish et al. have demonstrated for the first time through a well-controlled RCT the beneficial effect of an intensive lifestyle changes in AD patients.¹⁰² The synergy from combining multiple lifestyle factors in an intervention could lead to more profound and sustainable health improvements in AD patients.

Another factor that we have to consider is that in most of the studies included in this systematic review, the diagnosis of AD patients was established without the use of biomarkers. The correct diagnosis of AD is crucial for the proper management of the disease and the planning of treatments. In fact, the National Institute on Aging and Alzheimer's Association (NIA-AA) has recently revised and established diagnostic recommendations based on biomarkers for the preclinical, mild cognitive impairment, and dementia stages of AD.¹⁰³ The use of biomarkers, such as amyloid biomarkers or pathologic tau biomarkers, can provide objective evidence and help distinguish AD stages and AD from other forms of dementia. However, in current practice, the use of these biomarkers is not widespread due to their high cost, lack of access to advanced technologies, and lack of standardization in diagnostic procedures. This deficiency can lead to incorrect or delayed diagnoses, which in turn can result in inadequate treatments and faster progression of the disease. Furthermore, the lack of accurate diagnosis can hinder the proper inclusion of patients in clinical trials, affecting research and the development of new therapies. Therefore, it is essential to promote the use of biomarkers in clinical practice to improve diagnostic accuracy and patient outcomes. We have also to consider that a large portion of RCTs revised do not measure biological markers. Biomarkers, such as Aβ and tau proteins provide direct information about the underlying pathological mechanisms of the disease, can be detected in the early stages, allowing for early intervention and more accurate monitoring of disease progression. Furthermore, biological markers can help evaluate the efficacy of treatments in a more objective and quantifiable manner, facilitating the development of more specific and effective therapies. In contrast, other parameters like cognitive and behavioral changes are often more subjective and can be influenced by multiple external factors, limiting their accuracy and usefulness in AD research and treatment.

The control and intervention groups in all studies consist of patients with AD; therefore, the starting conditions of both groups should be similar. However, it is important to note that most of the interventions included in this systematic review do not have a placebo per se. Except for some dietary interventions, such as probiotics or vitamins, where the control groups receive a placebo capsule, dietary interventions, exercise interventions, cognitive training, and other therapies such as music, mindfulness, etc., do not permit the use of ‘placebos’. In exercise interventions, the most common control groups treatment is the ‘continuation with the daily routine’ or ‘usual care’; however, creating a sham group for exercise studies is challenging.^104,105 Moreover, physical activity impacts mental health, making it complex to determine the extent to which psychological benefits from physical exercise are attributable to placebo effects. Similarly, other interventions, such as acupuncture or the use of devices, face analogous challenges.¹⁰⁴ For dietary interventions, nutritional advice is often used as the control technique; however, this may not be optimal for such studies. Instead, more rigorously designed control diets would be necessary to implement placebo controls in dietary interventions.¹⁰⁶

To understand the modulatory factors of AD, further research is imperative to identify interventions capable of significantly mitigating its symptoms and progression. Our systematic review suggests that lifestyle interventions are associated with moderate improvements in the quality of life for individuals affected by AD, but do not lead to significant changes in cognitive function. In fact, future studies with long-term follow-ups and consistent intervention measures over time are needed to establish a stronger evidence base for cognitive function improvement in AD patients.

This review has several limitations. Firstly, our search strategy may have missed abstracts that did not clearly specify the various parameters considered in this review. This omission could have influenced the number of studies included in the analysis, as researchers might have chosen not to disclose these results due to their lack of statistical significance. Additionally, the trials included in this review ranged in duration from 4 weeks to 24 weeks, reflecting significant variability in the type of intervention and the outcomes achieved. For certain activities, such as light exposure and mindfulness, we were unable to explore the sources of heterogeneity between studies due to the limited number of studies available. Furthermore, the studies considered in this review were conducted primarily in the US, Australia, Europe, and other high-income countries, limiting the generalizability of the findings, particularly to low- and middle-income countries.

Finally, while the risk of bias is generally low for most of the studies included in this review, there are other factors that are not accounted for in the assessment of bias and should be considered: (1) many studies do not calculate sample sizes, which can affect the statistical power and reliability of the results; (2) dietary factors are often not considered in exercise trials and vice versa, as well as other factors such as body mass index or initial muscle strength; (3) there is considerable variation in the statistical analysis used among studies, particularly regarding covariate analysis.

Future studies in each area should prioritize reproducible research practices, such as protocol registration and adherence to common intervention criteria, to enhance the reliability and comparability of findings across studies.

Conclusions, limitations, and future research

Our review of RCTs suggests that there are numerous lifestyle interventions that could enhance the quality of life for AD patients, addressing both cognitive and executive function levels. However, the number of studies for each intervention type is limited, with variations in duration, dosage, types of exercise, training methods, and devices used. Future studies with long-term follow-ups and consistent intervention measures over time are needed to establish a stronger evidence base for cognitive function improvement in AD patients. Additionally, studies involving larger and more diverse populations, with equal consideration given to gender, are necessary to enhance generalizability and determine the dose-response relationship of interventions for AD symptom improvement. Lastly, further high-quality RCTs exploring simultaneously different lifestyle interventions are required to determine whether synergistic effects between interventions could constitute a comprehensive treatment program for AD patients, ultimately enhancing their quality of life and cognitive function. A limitation of our study is that we only included articles written in English and Spanish, as these are the languages we can clearly understand, and three studies were discarded due to language barriers.

Supplemental Material

sj-docx-1-alz-10.1177_13872877241292829 - Supplemental material for A systematic review of lifestyle-based interventions for managing Alzheimer's disease: Insights from randomized controlled trials

Supplemental material, sj-docx-1-alz-10.1177_13872877241292829 for A systematic review of lifestyle-based interventions for managing Alzheimer's disease: Insights from randomized controlled trials by Sara Martínez-López, Mariangela Tabone, Sara Clemente-Velasco, Maria del Rocío González-Soltero, María Bailén, Beatriz de Lucas, Carlo Bressa, Diego Domínguez-Balmaseda, Juan Marín-Muñoz, Carmen Antúnez, Beatriz G. Gálvez and Mar Larrosa in Journal of Alzheimer's Disease

Footnotes

Acknowledgments

Figure 2 was created in BioRender. Pardo M (2024) https://BioRender.com/l71l897.

ORCID iDs

María Bailén

Beatriz de Lucas

Mar Larrosa

Author contributions

Mar Larrosa (Conceptualization; Funding acquisition; Investigation; Methodology; Project administration; Writing – original draft; Writing – review & editing); Sara Martínez-López (Data curation; Methodology; Writing – original draft); Mariangela Tabone (Methodology; Visualization; Writing – original draft); Sara Clemente-Velasco (Methodology; Visualization; Writing – original draft); Maria del Rocío González-Soltero (Methodology); María Bailén (Methodology); Beatriz de Lucas (Methodology); Carlo Bressa (Methodology); Diego Domínguez-Balmaseda (Methodology); Juan Marín-Muñoz (Supervision); Carmen Antúnez (Supervision); Beatriz G. Gálvez (Conceptualization; Methodology; Supervision; Writing – review & editing).

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Spanish Ministry of Science and Innovation with the PID2021–123700OB-I00 research project.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

The data supporting the findings of this study are available within the article and/or its supplemental material.

Supplemental material

Supplemental material for this article is available online.

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