Virtual reality interventions and their effects on the cognition of individuals with Alzheimer's disease: A systematic review and meta-analysis

Abstract

Background

Dementia due to Alzheimer's disease (AD) is the most prevalent neurocognitive disorder in the world and impacts the individual's cognitive functions and functionality in the early stages of the condition. Virtual reality (VR) interventions can assist in non-pharmacological treatment in a more ecological way, positively impacting cognitive abilities. However, there are few studies on VR exclusively involving people with AD in randomized controlled trials.

Objective

To evaluate the effects of VR intervention on the cognitive functions of people with AD.

Methods

A systematically conducted search was carried out in MEDLINE, EMBASE, BVS, Web of Science, and Scopus. Eligible studies were randomized controlled trials comparing the efficacy of VR and traditional cognitive interventions in people with AD. Methodologic quality was assessed with the Cochrane risk of bias tool, and outcomes were calculated as risk ratios (for dichotomous outcomes) and mean differences (for continuous outcomes) with 95% confidence interval.

Results

A total of three randomized controlled trials with 75 participants were included. An improvement in the performance of the VR group was observed in memory, especially when comparing the usual treatment [MD = 0.99; CI95%: 0.33; 1.66; I²= 0%]. VR has little or no effect on participants’ executive function [MD = 1.36; 95%CI: −1.12; 3.85; I²= 0%] compared to the usual treatment.

Conclusions

Our study results cautiously suggest, despite the small number of participants, that VR intervention may be a suitable memory treatment for individuals diagnosed with AD.

Keywords

Alzheimer's disease cognition dementia memory virtual reality

Introduction

Dementia is a neurodegenerative disease that impacts cognitive and behavioral functions over time.¹ It is estimated that the number of people with dementia will triple by 2050, increasing from 50 million to 152 million individuals.² It is estimated that mental illnesses account for over 10% of health-related expenditures worldwide.^3,4 Even though several conditions can lead to dementia, Alzheimer's disease (AD) accounts for more than 70% of cases.⁵ It is worth mentioning the AD treatment cost of care was indicated as $305 billion for 2020 and the total cost is projected to reach more than 1$ trillion by 2050.⁶

The medical assessment of cognitive screening may not always capture signs associated with cognitive decline in mild AD. A neuropsychological evaluation is recommended to subtle symptoms, including non-amnestic ones.^7,8 Nevertheless, significant barriers are still observed in assessing and diagnosing these conditions. Traditional neuropsychological tests and interventions have been used for cognition for many years. Individuals with AD often struggle to adhere to and stay motivated when using cognitive tests, which can be challenging. Furthermore, these tests may need more ecological validity, meaning they may not accurately measure the cognitive decline in daily life.⁹

As a neurocognitive disease, AD presents progressive declines in episodic memory and other functions, as well as functional decline, impacting autonomy and independence.¹⁰ Researchers around the world are focused on finding ways to treat AD and aiming to improve cognitive function. There are many non-pharmacological treatments available. For example, psychological therapies designed to enhance cognitive function have been used for decades to reduce the impact of cognitive decline.¹⁰ These interventions can be more personalized, as seen in cognitive rehabilitation,¹¹ which is a well-documented technique, evidence-based, and cost-effective, that can improve cognition and quality of life in older adults with dementia.¹² In this context, developing ecological tests for diagnosing and identifying cognitive strengths and weaknesses is essential.¹³ Virtual reality (VR) has existed since approximately 1960 and has become an increasingly popular tool, first applied in the healthcare field in the 1990s.¹⁴ Integrating VR into neuropsychological interventions could offer promising opportunities to improve cognitive rehabilitation and enhance the quality of life for individuals with AD. As a novel approach to treating these conditions, VR has gained recognition as a powerful tool in recent years, due to its potential to provide more cost-effective and comprehensive interventions.¹⁴

There are different levels of VR immersion: non-immersive, semi-immersive, and fully immersive.¹⁴ At all levels of immersion, scenarios are created to provide a sense of presence, resembling real life.¹⁵ The non-immersive level can be implemented using a conventional computer, where virtual environments are displayed on screens, and users control their actions using devices such as joysticks or keyboards.¹⁶ At the semi-immersive level, users interact with the virtual environment but maintain visual contact with the physical surroundings.¹⁷ This immersion can be implemented using a larger, broader screen projector with interactive features.¹⁸ At the immersive level, users experience complete immersion in the virtual environment, creating the sensation of living within that virtual world.¹⁹ In this highly immersive setting, users can observe physical projections around them and use instruments like VR goggles to achieve a profoundly immersive experience.¹⁴

Studies suggest that VR may be beneficial for assessing and intervening in people with AD and mild cognitive impairment (MCI).²⁰ A systematic review²¹ involving individuals at high risk for cognitive decline observed that VR facilitated improvements in attentional levels, executive function, and memory (visual and verbal). It also noted a reduction in symptoms of anxiety and depression. Another study²² demonstrated that VR could be an effective treatment for individuals with AD and mild cognitive impairment, particularly in terms of cognitive training. Therefore, VR simulates a real-life environment created by software that allows people to experience the sensation of being in a specific physical location at that moment.²³ Owing to its ability to replicate ‘realities’ pertinent to symptoms, VR may be particularly suitable for developing innovative test environments that blend authenticity with a high degree of standardization.²⁴ Amjad et al.²⁵ demonstrated significant results in the use of VR exergames in individuals with cognitive impairment, both for the Mini-Mental State Examination (MMSE, p = 0.003), the Montreal Cognitive Assessment (p = 0.0001), and the Trail Making Test (TMT-A, p = 0.02; and TMT-B, p = 0.0001) in the intervention group. A systematic review, conducted by Kruse et al.,²⁶ analyzed 22 articles, of which 6 utilized VR as an intervention to enhance cognition in people with AD. Improvement was observed in memory ability and overall cognition.

Furthermore, in VR, there is interaction between the user and the technology, where the individual can often speak, walk, and view the environment from various angles using specific controls and sensors.²⁷ Scenarios that are nearly impossible to simulate in a conventional neuropsychological assessment environment can be created. In individuals with AD, innovative resources can be developed to aid in diagnosis, non-pharmacological treatment, interventions, and even individual monitoring.²⁸ A study reports that VR can diagnose AD by presenting cognitive profiles of other peers and healthy controls.⁹ Furthermore, the devices can be used in a portable manner and applied to people with AD by professionals not from the health field and can also be conducted at home.^29,30 The VR tasks have been correlated with neuropsychological tests, indicating their potential use as a health device tool.^9,31,32

Increasingly, technology plays a significant role in healthcare services, such as assisting in diagnosing diseases. It is a promising tool for measuring cognitive performance, as individuals can perform real-world tasks within VR.^33,34 Although it is a widely studied topic today, VR is still relatively new, and more studies are necessary to analyze its effects on older adults with AD. For example, a meta-analysis by Papaioannou et al.²² noted the positive effects of VR training on people with MCI and AD. In addition, Wu et al.³⁵ observed that VR intervention possibly retards the progression of MCI to AD due to advanced cognition and routine function training, causing an improved overall cognitive function. An interesting finding was reported by Zhu et al.,³⁶ stating that VR enhanced cognitive and motor function in people with MCI or dementia. However, it did not reveal significant visual competency and gait performance results.

In addition to the immersive experience provided by VR, a significant reason for its promise in cognitive treatment is that real-life activities inspire many exercises performed and created in the virtual environment. Thus, tasks carried out in VR, such as meal preparation, shopping, planning, and spatial orientation, can be replicated in daily life. By repeatedly training the participants in a controlled environment, there is potential to facilitate the transfer of these learned skills from VR to real-world situations.

The literature review observed that a few randomized controlled trials have investigated VR intervention in people with AD. In this context, this systematic review with meta-analysis aimed to evaluate the randomized controlled trial (RCT) studies for investigating the efficacy of VR cognitive intervention in people with AD compared to traditional cognitive methods. This study focused exclusively on people with AD because it is the most prevalent dementia worldwide, affecting a larger number of older individuals. Moreover, dementia conditions often present diverse cognitive symptoms, which impact the analysis and reliability of results due to the heterogeneity of the samples.

Methods

The protocol of this systematic review and meta-analysis was registered at PROSPERO under the number CRD42023454402 and follows the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines.³⁷ The characteristics of each study were methodically extracted and compiled into tables, capturing the following data fields: participants, intervention, comparison (against control group), outcome, and study design (PICOS).

Criteria for considering studies for this review

Types of studies

All prospective RCTs in which VR was compared to traditional intervention methods such as conventional cognitive stimulation were eligible for inclusion, if at least one generally-accepted outcome measure was used. We did not exclude trials on the basis of language or year of publication. The PICOS strategy is a structured approach used in clinical research to formulate research questions and was employed in this study. In this case, the population (P) refers to individuals with Alzheimer's disease, characterized by cognitive decline, memory loss, and spatial navigation deficits. The intervention (I) being studied is virtual reality (VR), which aims to improve cognitive function through immersive simulations. The comparison (C) involves standard treatments that do not use VR, such as conventional cognitive therapies. The outcomes (O) of interest include improvements in memory, spatial navigation, and cognitive performance. The study design (S) preferred for this research is RCTs, providing the most reliable evidence for the effectiveness of VR in treating AD symptoms.

Types of participants

Participants diagnosed with dementia due to AD. Studies with diagnoses such as MCI or Mild Neurocognitive Disorder (term used in DSM 5) were not included. Likewise, studies with other types of Major Neurocognitive Disorders, such as vascular dementia, Lewy bodies, Parkinson's disease, among other conditions, were not included. Regarding age, we only included studies with individuals over 60 years old, men and women. Regarding the stage of dementia, all stages were covered in the studies.

Types of interventions

Studies that included older adults diagnosed with dementia due to AD and compared the effects of virtual reality (immersive, semi-immersive or non-immersive) to traditional cognitive interventions.

Types of outcome measures

According to the review methods used, this study selected outcome measures relevant to cognition. Studies that did not address topics on cognition were excluded. The results analyzed were those that assessed cognitive abilities such as global cognition, executive functions and memory. Neuropsychological scales and tests were applied pre- and post-intervention with VR. These same measures were evaluated before and after, without changes in the instruments used.

Electronic surveys

We searched the following trial records using the terms ‘virtual reality’ and ‘Alzheimer's dementia’, on March 2024. We accessed the following databases: MEDLINE (via PubMed) on March 16, 2024; BVS on March 16, 2024; Embase on March 17, 2024; Web of Science on March 20, 2024; and Scopus on March 20, 2024.

MEDLINE (via PubMed) (from 1946) using the search strategy:

#1 “Alzheimer Disease"[Mesh] OR Alzheimer Dementia OR Alzheimer Dementias OR Dementia, Alzheimer OR Alzheimer's Disease OR Dementia, Senile OR Senile Dementia OR Dementia, Alzheimer Type OR Alzheimer Type Dementia OR Alzheimer-Type Dementia(ATD) OR Alzheimer Type Dementia (ATD) OR Dementia, Alzheimer-Type (ATD) OR Alzheimer Type Senile Dementia OR Primary Senile Degenerative Dementia OR Dementia, Primary Senile Degenerative OR Alzheimer Sclerosis OR Sclerosis, Alzheimer OR Alzheimer Syndrome OR Alzheimer's Diseases OR Alzheimer Diseases OR Alzheimers Diseases OR Senile Dementia, Alzheimer Type OR Acute Confusional Senile Dementia OR Senile Dementia, Acute Confusional OR Dementia, Presenile OR Presenile Dementia OR Alzheimer Disease, Late Onset OR Late Onset Alzheimer Disease OR Alzheimer's Disease, Focal Onset OR Focal Onset Alzheimer's Disease OR Familial Alzheimer Disease (FAD) OR Alzheimer Disease, Familial (FAD) OR Familial Alzheimer Diseases (FAD) OR Alzheimer Disease, Early Onset OR Early Onset Alzheimer Disease OR Presenile Alzheimer Dementia

#2. “Virtual Reality"[Mesh] OR Reality, Virtual OR Virtual Reality, Educational OR Educational Virtual Realities OR Educational Virtual Reality OR Reality, Educational Virtual OR Virtual Realities, Educational OR Virtual Reality, Instructional OR Instructional Virtual Realities OR Instructional Virtual Reality OR Realities, Instructional Virtual OR Reality, Instructional Virtual OR Virtual Realities, Instructional

#3 - #1 AND #2

The additional search strategies can be found in the Supplemental Material.

Reference lists

We checked the references of the included studies and searched for articles that could be added, with relevant data.

Data collection and analysis

Study selection

Once an article was identified for possible inclusion, the citation was recorded and the article was downloaded in PDF format. All articles were in English and the reviewers had knowledge of this language to the point of allowing adequate reading, without having to translate everything into their mother tongue. Two reviewers (VDS and ACC) assessed each study independently to see which studies met the inclusion criteria for this review. The conflicts were solved through an online meeting, where each person was able to express their perceptions and in the end, they reached a consensus. One publication was found to be a duplicate only later, as the title was different from the published magazine, and this was only possible to observe when reading the full article.

Data extraction and management

We designed and tested data extraction forms in an Excel table (Microsoft Office) based on the relevant data from the articles to detect the results with greater precision. We tested the table with the final data. The pair performed data extraction. Conflicts observed in the description of the results were solved, and doubts related to the studies discussed.

The following information was extracted from each study:

study information: author, country, year and type of study

information about participants: gender, age group and educational level.

Information that characterizes the intervention: type of treatment, form of application, duration, and control treatment.

Information that characterizes the participants: number of participants enrolled in each group, recruitment method, degree of AD dementia, number at final assessment, percentage of participants not counted.

Result data - information on the results of neuropsychological tests and scales used pre and post-intervention, with number of participants, mean, standard deviation. As well as all changes from each group.

Assessment of risk of bias in included studies

Two reviewers (VDS and ACC) independently assessed the risk of bias of each included article using version 2 of the Cochrane “Risk of Bias” (RoB2)³⁸ tool, with recommendations from the Cochrane Handbook for Systematic Reviews of Interventions.³⁹ Disagreements were solved by a consensus held through a virtual meeting and we used the following definitions to assess the risk of bias: bias resulting from the randomization process; bias due to deviations from intended interventions; bias due to lack of outcome data; bias in measuring the outcome; bias in the selection of reported studies. We focused on evaluating the effect of attribution to interventions at baseline (the “intention-to-treat effect”). For signaling questions within each domain for each outcome, we provide one of the five possible answers in the RoB2 tool³⁸ (“Yes”, “Probably yes”, “No”, “Probably no” and “No information”), judging as “Low risk of bias”, “Some concerns” or “High risk of bias”. According to the algorithm output, the overall risk of bias judgment for each outcome was the least favorable assessment across all domains (Figure 1).

Figure 1.

Risk of bias RoB2. In light gray: some concerns, in dark gray: low risk of bias.

Measures of treatment effect

The analyzes have attempted to include all people who were randomized to immersive, semi-immersive, or non-immersive VR with control treatments (a intention-to-treat analysis). Where continuous data such as analyzed performances on neuropsychological tests were extracted in the form of mean and standard deviation. The adverse symptoms that may occur in people who use any intervention in VR were not analyzed in this study.

Use of different cognitive tasks

Due to the use of different tests employed for memory assessment, the combined effect measure was calculated based on standardized mean differences.

Dealing with missing data

No included study had missing results data. Only one study did not make clear the educational level of all included individuals.⁴⁰ For example, education below the primary level can be any amount less than four years. Therefore, an estimate calculation was carried out to determine the participants’ general average level of education.

Data synthesis

We performed statistical analysis according to the statistical recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions.³⁹ We compiled risk ratios (for dichotomous outcomes) and mean differences (for continuous outcomes) with 95% CIs of individual trials using a random-effects meta-analysis (when results of two or more similar studies can be pooled). We used an intention-to-treat analysis as far as possible. Data were analyzed using meta package on R program.⁴⁰

Subgroup analysis and heterogeneity investigation

Only one study⁴¹ had heterogeneous groups from a statistical point of view (p < 0.05) in relation to global cognition.

Sensitivity analysis

Due to the number of studies included in this review, we did not perform a sensitivity analysis.

Results

Search results

We identified a total of 1275 references through database searching. We used the following databases for conducting the research: PubMed, Embase, BVS, Web of Science, and Scopus. We found 17.1% articles in PubMed, 11.0% in Embase, 7.3% in BVS, 23% in Web of Science, and 41.6% in Scopus. These percentages refer to the number of studies found in the databases before the removal of duplicate articles. The search covered March 2024 to April 2024 and consisted of 1 search, plus 4 studies identified by citation searching. We removed 523 duplicate records before the screening.

We screened a total of 752 partial-text articles for eligibility (Title and Abstract). There were 63 conflicts regarding the articles, which were solved with a high level of agreement between the two reviewers (VDS and ACC). We excluded 689 for reasons: 63 did not meet the inclusion criteria (RCT articles using VR with elderly individuals with AD); 11 studies were unable to be accessed and awaited classification while further information was being obtained; 4 citation searching were excluded for reason (2 wrong study designs and 2 wrong populations).

We screened 52 full-text articles for eligibility and 49 were removed for reason (22 wrong populations, 26 wrong study designs, 1 repeated article). See Figure 2 for a PRISMA³⁷ flow diagram.

Figure 2.

PRISMA flowchart.

Included studies

Design

The duration of the trials varied from 1 day⁴² to 6 weeks 41. The duration of VR application varied between studies: from 2 min,⁴² 20 min,⁴³ and 45 min⁴¹ per session. No studies were conducted under double-blind conditions. In these cases, the evaluators and participants knew about the experiment they were carrying out.

Sample sizes

The number of participants included in individual RCTs varied from 17⁴¹ to 30.⁴² The average number of participants was 25. One study included healthy participants in the sample⁴³; however, in the analysis, it evaluated the group with AD, dividing into two groups: the group that received the VR intervention and the group that received the traditional intervention.

Context

In total, the three studies were carried out in different centers. The study by Oliveira et al.⁴¹ was made in Portugal, at Santa Casa da Misericórdia from Amadora (Center SCMA); the study by Serino et al.⁴³ was carried out in Italy, in a social senior center; the study by Xu & Wang⁴² was carried out in China, at the Changsha Armar Dementia Care Center and the Dementia Department of Changsha Geriatric Rehabilitation Hospital.

Participants

The three RCTs had a total of 75 participants. However, we excluded healthy individuals who were part of a study. Therefore, we used samples only of people with AD for our analyses. In this case, 30 individuals performed the VR intervention, and 27 participated in the control group. Across all included studies, there were 57 participants (n = 30 for VR intervention; n = 27 for the control group). The minimum age was 60 years. There was no maximum age to participate in the study. The average age across the studies was 82.19 years.

All studies contained more women than men. In the study by Oliveira, et al.,⁴¹ there were 7 women and 3 men in the experimental group, and in the control group, 5 women and 2 men. In the study by Serino et al.,⁴³ there were 9 women and 1 man in the intervention group, and in the control group there were 8 women and 2 men. In the study by Xu and Wang,⁴² in the intervention group there were 5 women and 5 men, and in the control group there were 2 men and 8 women. All studies reported inclusion criteria. Among these criteria, participants needed to have a preserved visuospatial ability at a certain level to be able to carry out VR interventions. Exclusion criteria almost always included a history of serious psychiatric disorders, or other conditions such as stroke or traumatic brain injury. As well as severe impairments in language and motor skills.

Interventions

Among the trials identified, all of them assessed cognition as the basis for initiating the study. However, one study⁴² did not use a traditional neuropsychological instrument to evaluate the intervention. Two studies^41,43 evaluated cognition with well-known parameters, such as the Frontal Assessment Battery (FAB), which is an instrument that aims to detect executive dysfunction associated with the frontal lobe through the assessment of functions such as conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy.⁴⁴ In addition to this parameter, the three studies used the MMSE,⁴⁵ which is a cognitive screening instrument used worldwide. The Serino et al. study⁴³ assessed visuospatial memory using the Corsi Cubes Test.⁴⁶ This task assesses visuospatial short-term memory and visuospatial working memory skills.

In terms of VR, the study by Oliveira, et al.⁴¹ carried out the intervention by stimulating cognitive skills related to Instrumental Activities of Daily Living (IADL),⁴⁷ with a non-immersive VR program, using a 17-inch computer screen. The sessions present different levels of difficulty that progress throughout the intervention. In this study, they used the Lisbon Systemic Battery (SLB),⁴⁸ which promotes cognitive functioning with cognitive tasks and exercises that simulate IADL. This battery has already been used in other studies, which point to the idea that it is a tool capable of improving cognition, especially with regard to executive functions. The IADLs in the study include the following modalities: Morning hygiene, Shoe closet test, Wardrobe test, Memory test, Virtual kitchen, Television news, Grocery store, Pharmacy and Art gallery test. The first six tasks were carried out inside a virtual apartment. The other tasks were carried out outdoors, in which participants navigated to each place in the virtual environment.

In the study by Serino et al.,⁴³ the VR non-immersive intervention was also carried out using a computer. A city was portrayed in the virtual environment, which was built around a square with a fountain and a bar, which represented the starting point of navigation for participants. There were buildings and stores in the virtual environment. The administrator, who was a neuropsychologist, then asked the participant to locate three objects that were hidden. After locating, they were instructed to keep where each object was. They were then asked to remember where they were when entering the virtual city from another starting point. The treatment was adapted according to the level achieved by each participant. The sessions lasted around 20 min. This intervention was based on NeuroVirtual 3D, which is an extension of the NeuroVR software.⁴³

Participants in a study by Xu and Wang⁴² were divided into three groups, all aimed at improving autobiographical reminiscence memory. The first group received VR immersive intervention, where they were placed in a virtual reminiscence room resembling a rural Chinese environment from the 1970s. The room featured various objects characteristic of Chinese culture from that time, and the 3D modeling was created using 3DS Max software. Participants wore a VR headset and assessed the intervention with glasses that could not last more than two minutes due to eye strain. The second group received cognitive intervention using photos, with 20 color photos printed featuring objects identical to those used in the virtual environment room. The third group did not receive any visual stimuli. In this study, only the first and third groups were analyzed for the results, as the difference between the interventions was greater in this case, providing a better analysis of the data regarding the effect of VR on participants with AD.

Intervention duration

The studies exhibited considerable variation in the duration of the VR interventions. Oliveira et al.⁴¹ implemented the intervention over a span of 6 weeks, with sessions conducted twice a week, each lasting 45 min. Conversely, Serino et al.⁴³ administered 10 sessions over 3 to 4 consecutive weeks, three times a week, with each session lasting 20 min. Xu and Wang⁴² conducted the intervention in a single day, utilizing VR for 2 min.

Outcomes

All studies used a single measure to analyze a specific cognitive function compared to the effect of a virtual reality intervention. All studies intended to evaluate the effectiveness of the intervention on the cognition of people with AD and reported results taking into account a pre- and post-virtual reality intervention assessment.

In one study, an initial training session was conducted before starting the experiment with virtual reality. This training session consisted of a brief two-minute training session.⁴³

Adverse effects

It is known that some adverse events may occur with individuals who use VR, such as signs of nausea and dizziness. There are some questionnaires that can measure this, such as the Virtual Reality Sickness Questionnaire (VRSQ).⁴⁹ This nausea can occur when there is an incongruity between the stimuli coming from the vestibular, visual and proprioceptive systems from an unfamiliar movement of the body, or even a distorted spatial perception, thus generating a conflict in the sensory areas of the brain.⁵⁰

Of all the studies, only one used a questionnaire to assess sickness.⁴² This particular study evaluated the adverse symptoms with VRSQ, and the results showed low rates (M < 0.50).⁴² In the other studies, we did not observe this type of assessment.

Table 1 presents additional details about the characteristics of the study and individual results.

Table 1.

Description of studies.

Author	Objective	Design	Outcomes	Participants	VR intervention	Instruments	Results
Oliveira et al. 2021³⁶	To explore the effect of VR-based cognitive stimulation on people with mild to moderate AD, using ecologically oriented approaches depicting IADL	Two-arm parallel design with A and B point assessment (Pilot randomized controlled trial) Non-immersive VR	Primary: executive functions Secondary: global cognition, functionality, depression, and dementia rating.	Mild AD n = 7, Moderate AD n = 8 and questionable AD n = 2, with a mean age of 83.24 years, SD = 5.66.	Pilot randomized controlled trial involved 17 participants from residential care homes who were divided into an experimental group receiving VR cognitive stimulation (n = 10) and a control group (n = 7) receiving usual care. Twelve cognitive stimulation sessions delivered by clinical neuropsychologists for 45 min sessions, distributed over two days a week, with a dosage of approximately 9 h.	Neuropsychological assessment was carried out at the baseline and follow-up using FAB, TMT, MMSE, IADL, CDT	Preliminary results suggested an improvement in overall cognitive function in the experimental group, with a significant effect size indicating a large effect on global cognition (MMSE Δmean = −1.20; SE = 0.51; p = 0.033), but no improvement in executive functions or specific cognitive functions (FAB - no statistically significant main (p > 0.05) or interaction effects (F(1, 15) = 2.032; Eta²_p= 0.119; p = 0.174) (TMT part A (Z = −2.121; p = 0.063) and TMT part B (Z = −1.342; p = 0.50).
Xu and Wang 2020³⁷	To examine the efficacy of virtual reality (VR)-based reminiscence therapy in improving autobiographical memory among Chinese participants with AD.	Randomized controlled trial. Immersive VR	Primary: autobiographical memory Secondary: motivation and sickness symptoms	30 AD participants. Age: VR = 76.7 y SD 5.5 Photo = 79.4 years SD 2.0 Control = 78.5 years SD 3.4	VR-based reminiscence therapy (n = 10), photo-based therapy (n-10), and a control group (n = 10). Techniques of 3D modeling and rendering were used to recreate scenes from 1970s China. In the VR group, the stimulus was displayed using HTC Vive Focus headset. The Photo group used 20 color print photos in which the reminiscence objects were identical to those in the virtual reminiscence room. In the Blank group, there was no visual stimuli. Stimuli (VR or photos) were provided to the patients for 2 min.	MMSE Autobiographical Memory was collected from a free narrative recount of a personal life event related to the presented stimuli.	VR-based reminiscence therapy was effective for improving autobiographical memory (VR group (M = 3.00, SD = 2.06, p = 0.008) and Photo group (M = 2.60, SD = 1.78, p = 0.027; (M = 0.90, SD = 0.74. However, there was no significant difference between the VR and the Photo groups (p > 0.05). Participants showed significant pleasure for the VR than for the photos, and reported negligible sickness symptoms
Serino et al. 2017³⁸	To assess the effectiveness of a VR-based training protocol aimed at enhancing the synchronization of allocentric and egocentric spatial representations in people with AD	Phase I Pilot randomized clinical trial Non-immersive VR	Primary: long term spatial memory	28 participants (20 with AD, 8 healthy older adults). Age: VR Group-AD = 86.60 years SD 6.13; Control Group-AD = 88.70 years SD 3.59; VR normal age group = 86.62 years SD 6.19	VR training AD (n = 10), VR training normal age (n = 8) and control group AD (n = 10). The training involved a 10-session program over 3–4 weeks. During each session, participants were asked to complete two parts: an “encoding phase” and a “retrieval phase”. From the center of a virtual city, they were required to locate one, two or three hidden objects. They were then instructed to memorize the position of these objects. In the retrieval phase, participants were asked to retrieve the position of the objects identified in the first phase, by entering the virtual city from another starting point.	MMSE, the phonemic verbal fluency and categorical verbal fluency test, FAB, the Attentional Matrices Test, the Digit Span Test, the Corsi Block Test	VR Group-AD scores were significantly better than Control Group-AD scores on the Corsi Block Test (p = 0.035). AD participants in the VR training group showed significant improvements in long-term spatial memory. The healthy older adults also showed enhanced executive function.

AD: Alzheimer's disease; VR: virtual reality; FAB: Frontal Assessment Battery; TMT: Trail Making Test; MMSE: Mini-Mental State Examination; IADL: Instrumental Activities of Daily Living; CDT: the Clock Drawing Test.

Risk of bias in included studies

All studies raised some concerns, mainly regarding the randomization process and the lack of a blinding stage. The studies also did not present registration on the clinical trials base, which did not allow verification of the protocol used to conduct the study.

Allocation

There was also no specification regarding the participants’ allocation process. For this reason, all studies were classified as some concerns.

Blinding

No study included blinding participants or those carrying out the intervention. This data is expected, as the VR intervention has a methodology that is very different from other methods. Therefore, whoever was part of this group knew they were receiving the intervention. Likewise, those who did not receive this intervention knew they were part of another group that did not use VR.

Incomplete results data

There was no dropout reported in any study after the start of the intervention.

Selective reporting

There was no report of records from known clinical trial bases, such as https://clinicaltrials.gov. This did not allow us to verify if there was selective reporting.

Effects of interventions

The outcome measures of interest estimated the effects on people with AD cognition, comparing clinical data collected before and after the VR intervention. The parameters used for the evaluation were test scores. In AD, even a slight improvement can be significant since the disease is neurodegenerative, and cognitive decline is expected over time. However, the observed effects were analyzed on a one-time basis and had not been tested over time.

Virtual reality and executive functions

For this outcome, two studies were combined^41,43 totaling results from 37 participants (n = 20 in the VR intervention and n = 17 in the usual treatment). Both studies used the FAB instrument,⁴⁴ which assesses executive functions. VR has little or no effect on participants’ FAB [MD = 1.36; 95%CI: −1.12; 3.85; I2 = 0%] compared to usual treatment (Figure 3).

Figure 3.

Meta-analysis of executive function data.

Virtual reality and memory

Two studies^42,43 evaluated the effects of VR on memory. In this case, the two articles focused on different types of memory: autobiographical memory⁴² and short-term visuospatial memory.⁴³ An improvement in the performance of VR group was observed, especially when comparing the usual treatment [MD = 0.99; IC95%: 0.33; 1.66; I²= 0%] (Figure 4).

Figure 4.

Meta-analysis of memory data.

Discussion

The main objective of this review was to analyze and compare the effects of VR intervention in people with AD compared to other traditional methods of cognitive intervention. We observed the existence of many VR studies demonstrating improvements in cognitive functions in general with the population with MCI and other dementias. However, few studies still focus on a single type of etiology, resulting in many heterogeneous results. This lack of RCT compromises the evaluation of the effectiveness of VR on the cognitive abilities of people with AD.

After conducting a meta-analysis, an improvement in overall cognitive function was observed, with a significant effect size indicating a large effect on memory but no improvement in executive functions (FAB).⁴¹ In addition, it was also noticed that VR had a positive impact on visuospatial short-term memory⁴³ and autobiographical long-term memory⁴² compared to the usual treatment. The differences observed in the effects of the three studies can be attributed to the methodological differences among them. Two studies used non-immersive programs^41,43 while the other used an immersive program.⁴² Therefore, there is heterogeneity in VR studies regarding the level of immersion, the technology used, and the nature of the VR training programs. It is also important to highlight the difference in the duration of each study, which may have influenced the analysis in some way. For this reason, this variation may interfere with the outcomes of the interventions. Although efficacy has been found in memory, this variation might hinder the measurement of effectiveness in other cognitive abilities, such as executive functions. One study⁴² conducted an intervention that lasted for two minutes, whereas others conducted sessions that spanned over weeks. It is essential to emphasize that studies with brief intervention durations yield immediate effects, whereas extended interventions generally lead to sustained effects. However, these aspects of duration must be further investigated in more homogeneous RCTs. Future research should standardize the intervention lengths to understand better the differential impacts of short-term versus long-term VR interventions. Previous studies have shown that different types of training can impact different cognitive domains because specific platforms may stimulate one cognitive domain more than another.²² Hence, the type of technology used may also influence the results of VR studies. Another possible explanation for the differences found in the cognitive domains is the nature of autobiographical memory in AD. Autobiographical memory is generally one of the last types of memory affected by AD, which means that old memories and facts of one's life story tend to remain intact for many years after the onset of the disease. This point may explain why tests related to autobiographical memory often yield better results than tests related to executive functions. Furthermore, our results are consistent with previous research on the benefits of VR training for individuals with dementia regarding memory²² but not about improvements in specific cognitive domains, such as executive function.

A major concern is the adaptation of people with AD to the use of VR instruments. There were no problems regarding VR's applicability to people with AD in these three studies. It is worth mentioning that only one study⁴² collected possible undesirable effects on participants. Furthermore, there were a small number of participants in the studies, and the RCTs were only pilot studies, so caution should be taken when considering the conclusions regarding efficacy. There was no analysis or separation of samples based on the AD severity. Another important point is regarding the cognitive task measures, which were not the same across the three studies. The duration of each intervention and the level of immersion in VR also differed, which should also be considered. Previous research reports that people with AD tend to perform worse when using more immersive technologies compared to younger individuals, who show no significant difference between immersive and non-immersive technologies.^9,14,16 Immersive applications can be more challenging than conventional methods, hindering performance, particularly in clinical populations. Technology like VR might be difficult for older and clinical populations due to cognitive limitations, physical restrictions, and perceptual challenges. Further studies should evaluate the adverse effects of VR in AD to develop procedures designed to facilitate its possible adaptation difficulties.

It is important to note that the conclusions drawn from this review are limited by the fact that only a few articles were included. This point highlights the need for further studies to enhance our understanding of the field. We conducted a rigorous and cautious search, which made it even more important to expand and deepen our knowledge through additional research.

Despite the limited research available, VR has the potential to improve the cognitive abilities of people with AD. This systematic review may connect potential perspectives to the requirement for further development of these studies in the future with a more robust methodology. Additionally, the evidence analyzed in this systematic review suggests that VR interventions may be used with some caution in individuals with AD to provide cognitive rehabilitation more ecologically.

Conclusions

The major significance of this study is to demonstrate the relevance of discussing new cognitive treatments in the most prevalent type of dementia worldwide. Additionally, this systematic review sought only RCT studies, aiming for high scientific rigor. Most studies on VR in neurodegenerative conditions combine diagnoses of dementias, which are themselves vastly different in terms of proteinopathy, symptoms, and disease progression.

According to the findings, VR may positively impact memory compared to traditional interventions. However, no significant results were found concerning executive functions. Hence, a well-established understanding of the effectiveness of VR on all cognitive abilities of people with AD still needs development. Further studies should also aim for a more comprehensive measure of cognitive assessment, such as tests widely used and reported in the scientific literature for cognitive screening. Additionally, they should analyze the disease severity in each patient and be able to stratify the samples for a more reliable analysis. Therefore, more research is necessary to explore the underlying mechanisms of this treatment, expand scientific evidence, and help the world's population in the treatment of this form of dementia.

Supplemental Material

sj-docx-1-alz-10.1177_13872877241299037 - Supplemental material for Virtual reality interventions and their effects on the cognition of individuals with Alzheimer's disease: A systematic review and meta-analysis

Supplemental material, sj-docx-1-alz-10.1177_13872877241299037 for Virtual reality interventions and their effects on the cognition of individuals with Alzheimer's disease: A systematic review and meta-analysis by Vanessa Daudt Santos, Adriana Coelho Costa, Nelson Carvas Junior, François Jean Delaere, Sebàstien Serlet and Marcia Cristina Nascimento Dourado in Journal of Alzheimer's Disease

Footnotes

Acknowledgments

Marcia Cristina Nascimento Dourado receives research funding from The National Council for Scientific and Technological Development (CNPq) and Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ) grant number E-26/204.059/2024.

ORCID iDs

Sebàstien Serlet

Marcia Cristina Nascimento Dourado

Author contributions

Vanessa Daudt Santos (Investigation; Methodology; Writing – original draft); Adriana Coelho Costa (Investigation; Methodology; Writing – original draft); Nelson Carvas Junior (Formal analysis); François Jean Delaere (Conceptualization); Sebàstien Serlet (Conceptualization); Marcia Dourado, PhD (Project administration; Supervision; Writing – review & editing).

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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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