Nowadays, widespread access to health care systems and changes in living conditions have resulted in an aging population, leading to an increase in the prevalence of neurocognitive disorders (NCD) [1,2]. This phenomenon will lead to a societal change and place an additional burden on health care systems. Therefore, the main challenge at this time lies in the development of therapeutic measures at the pharmacological level that can prevent or halt the progression of Alzheimer disease (AD). However, so far, it has not been possible to find a pharmacological product that meets the safety and efficacy criteria necessary for large-scale use [3-5].

Conversely, numerous studies have shown that factors such as access to higher education, leading a healthy lifestyle, controlling cardiovascular risk factors, and being socially active can have a preventive effect by delaying the onset of symptoms and disease progression. In this context, it is of vital importance to identify emerging markers of AD that allow a diagnosis to be made in its preclinical stage.

The definition of preclinical AD varies, marked by criteria similarities and differences. It signifies the initial stage in the AD continuum, characterized by an extended asymptomatic phase with evidence of AD pathology, yet lacking cognitive, behavioral, or activities of daily living impairment (Table 1). Duration varies (6-10 years), contingent on onset age, and progression to mild cognitive impairment (MCI) hinges on factors like age, sex, and apolipoprotein E status. The complexity arises from not all those meeting preclinical AD criteria progressing to MCI or AD dementia, adding nuances to the predictive analysis [6].

In this sense then, early biomarkers are crucial for assessing and monitoring AD. These indicators, recommended by the National Institute on Aging and the Alzheimer’s Association, include the assessment of extracellular amyloid beta (Aβ) and hyperphosphorylated tau protein (p-tau) in the brain [7,8]. The latest guidelines classify neurodegeneration using biomarkers such as amyloid positron emission tomography, Aβ42 levels, tau protein, and neuroimaging techniques. Incorporating these biomarkers aids in the early detection and understanding of AD, aligning with evolving clinical practices and research efforts [9].

However, these biomarkers are expensive and not widely available in much of the world, and their results are not always consistent with the clinical manifestations of the patient, since even in the presence of positive markers, symptoms may not develop or may develop incompletely, and the time gap between the appearance of these biomarkers and the onset of symptoms has not yet been fully characterized.

Since the 1990s, there has been an increasing number of publications aiming to identify cognitive-behavioral markers of the shift from “normal” cognition (NC) to early symptoms of the disease [10-13]. In most studies, episodic memory appears as the domain that is altered in the first instance, reporting variability ranging from 20 [14] to 2 years prior to symptom onset [3,13,15-17].

More recent studies have explored other domains that could be altered earlier, especially visuospatial function and executive functions; in addition, spatial navigation tasks have appeared as a new domain with characteristics that encompasses the 2 previous ones [18-23]. Some studies have proposed to evaluate functional (such as modifications in expansive activities of daily living, changes in mobility patterns) and behavioral aspects, as well as conduct a more thorough analysis of companion reports, and even subjective memory complaints. However, there is little agreement on how to measure them and which ones exhibit true early marker behavior of the disease [24-26]. At this point, it is important to mention that the vast majority of studies are oriented to the diagnosis of NCD due to AD, with only a handful of studies exploring some characteristics of frontotemporal dementias or NCD associated with Parkinson disease, though these tend to have a much lower quality of evidence than studies for AD [27-32].

The most current approaches have incorporated artificial intelligence (AI) and machine learning (ML) tools with the purpose of developing multivariate models that take advantage of these advanced technologies to integrate neuroimaging results, neuropsychological variables, and biomarkers in the early diagnosis of AD [4,9,33-35]. In this context, the use of virtual reality (VR) environments presents a novel and yet underexplored opportunity. So far, they have mainly been used in therapeutic applications, but their potential in the field of diagnostics remains to be investigated [31,32,36-41].

This study aims to review prevalent neurocognitive markers for the preclinical stages of tauopathies, particularly AD. It also explores recent research on VR applications in this context and aims to identify the most evidence-supported tests for assessing valuable cognitive domains.

The steps followed for article selection are based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology [42], as evidenced in recently published literature reviews on similar topics [43,44]. References were obtained from the search for articles in PubMed and Google Scholar. Articles from the last 10 years were included, although we also included 2 articles published more than 10 years ago because of their importance in the field. In the first instance, the terms used for the search were “pre-dementia Alzheimer’s disease,” “dementia early diagnosis,” “dementia early diagnosis financial,” “benefits of early diagnosis of Alzheimer’s disease cost effectiveness,” “benefits of early diagnosis of Alzheimer’s disease,” and “early diagnosis of Alzheimer’s disease.” However, the articles obtained with these operators corresponded to those with primary treatment objectives or involving exclusively biological measures in different fluids, development of new neuroimaging modalities, or developments of AI and ML algorithms without including neuropsychological parameters. We opted for the search strategy proposed by Bastin et al [12] using the following keywords: ((memory AND longitudinal AND Alzheimer’s disease) AND (prodromal OR conversion OR preclinical)), ((mild cognitive impairment AND (Alzheimer’s disease OR dementia) AND neuropsychology AND (prediction OR longitudinal)), and (Alzheimer’s disease AND conversion AND neuropsychology).

When using these terms, none of the papers yielded results that included VR tools for diagnosis, so the pattern ((mild cognitive impairment AND (Alzheimer’s disease OR dementia) AND neuropsychology AND virtual reality)) was incorporated within the search strategy, finding 13 new papers of which 11 were incorporated, including 2 review papers that are discussed towards the end. Two papers were discarded because they were rehabilitation papers. The terms were used in English for most of the search engines, except for Google Scholar where the same terms were used in Spanish. Articles in both languages were included. As inclusion criteria, we selected those papers that made a longitudinal follow-up or an extensive review either through a systematic review or meta-analysis of the proposed topic. Those papers that could show conversion from NC to MCI or from MCI to dementia were weighted.

Based on this, 58 articles were selected based on the reading of the abstract. Studies conducted in animals, those that pursued primary treatment objectives, those conducted in patients with depression or other psychiatric/psychological comorbidity, those whose primary objective was to develop an AI algorithm, those that only used markers from blood, cerebrospinal fluid, urine, saliva, or other biological markers, and research theses were excluded. After reading the full text, those papers whose primary objective was the development of diagnostic imaging methods unrelated to neurocognitive variables (mainly related to functional magnetic resonance imaging [MRI], volumetry, cortical thickness) and without development of neurocognitive assessment (the tests used were not reported, they only showed raw scores of screening tests) were eliminated, as well as those papers that did not include a control group (MCI or normal aging or healthy controls).

Moreover, the Mendeley functionalities were used for the purpose of consolidating all references drawn from the various databases consulted. Subsequently, an integrated matching tool was used to identify and eliminate duplicates. In the initial screening phase, a preliminary selection of papers was made based on their relevance to the research question. To conduct this screening, the titles and abstracts of the papers were used to ascertain whether any of the 7 exclusion criteria set out in Table 2 were met. In instances where a decision was not immediately evident, the article was designated as a potential candidate for the subsequent phase.

Subsequently, the full text of all papers that had been deemed eligible following the screening phase was considered. This was considered to be the most appropriate set of papers on the topic, having overcome the exclusion criteria set out in Table 2.

The article selection process is outlined in Figure 1. This narrative outlines key discoveries from selected articles (Table 3 and Table 4)—studies without VR—categorizing the type of work and pinpointing the most early, sensitive, and specific neurocognitive variables according to each paper. Multiple cognitive variables, when presented, are organized by diagnostic profile. The chosen tests for variable measurements are specified. For a more detailed analysis of the reviewed articles, please consult the supplementary material (Multimedia Appendix 1). Moreover, a dedicated section and table are focused on findings related to VR and AI tools utilized for diagnosis (Table 5).

A large majority of articles present verbal episodic memory measured by different tests (Free and Cued Selective Reminding Test, California Verbal Learning Test, Rey Auditory Verbal Learning Test) as the earliest measure with the best sensitivity and specificity ratio for the detection of the preclinical stage of AD and the most recent works propose to support this measure with different neuroimaging formats, genetic profiling (apolipoprotein E), or markers (Aβ, tau, p-tau) in cerebrospinal fluid [11,12,46,49,50,53,60-62]. Among these papers, the one by Gagliardi’s team comparing different neuropsychological tests for the measurement of episodic memory stands out [51].

Harrington and collaborators [45] focused on executive functions using the Stroop test, conducted on individuals without apparent cognitive impairment. They compared those with positive amyloid in cerebrospinal fluid to those without pathology, revealing executive failure preceding memory issues. The study emphasized the absence of standardized protocols for cognitive neural vulnerability in preclinical stages.

The works of Bastin [12] and Gainotti [46] are 2 large review papers that attempted to identify early neuropsychological markers in preclinical and conversion AD, comparing cognitively healthy subjects with and without evidence of pathology. Both papers agreed that episodic memory is the earliest marker, followed by semantic memory, although the protocols used for its assessment differed.

One of the most outstanding articles found in this search is the work of Mistridis et al [63]. The article agrees that verbal episodic memory is an early marker of cognitive impairment, detailing the sequence of decline of various cognitive functions in subjects with NC who progress to MCI. Verbal memory declines about 8 years before MCI, followed by episodic learning, visual memory, and semantic memory about 4 years before MCI. Executive functioning and processing speed declined about 2 years before MCI diagnosis. This suggests that multiple cognitive domains are valuable in assessing preclinical AD.

Another paper that attempted to establish a timeline is that of Soldan et al [47], which used a composite score to evaluate 4 study groups of cognitively unimpaired patients, with the definitions of stage 0 (high Aβ and low tau), stage 1 (low Aβ and low tau), stage 2 (low Aβ and high tau), and suspected non-AD pathology (high Aβ and high tau). The article used linear mixed-effects models to estimate longitudinal cognitive composite scores among individuals in 4 preclinical AD groups. Adjusted for baseline factors, stage 2 individuals showed greater impairment and lower baseline scores compared to others, while stage 0, stage 1, and suspected non-AD pathology groups showed no significant differences. Involving 222 NC adults over 11 years, those in stage 2 (low Aβ, high tau/p-tau) showed markedly lower baseline scores and greater cognitive impairment, suggesting that abnormal amyloid and tau levels are necessary for cognitive differences in NC individuals.

Skills related to visuospatial function, which could prove important in the development of VR environments, were addressed in depth in the work of Caselli et al [14] and Iliardi et al [19]. The first study suggested that visuospatial function deteriorates 20 years before clinical signs of AD, aligning with early pathological changes. It aims to sequence neurocognitive alterations in preclinical stages of AD. The second article addressed the importance of assessing visuospatial working memory, anosognosia, and visuomotor control in patients with MCI, who show worse performance compared to healthy controls and sometimes like patients with dementia. Assessment of visuomotor abilities may help distinguish high-risk AD patients from nonrisk AD patients.

Wadley and colleagues [26] focused on processing speed impact on patient functionality, utilizing an ecological approach integrating neurocognitive and functional variables from professional observations, informant reports, and self-reports. They correlated these with neuroimaging and genetic markers, suggesting processing speed as a stronger correlation of everyday abilities than MRI patterns consistent with AD, and more accessible for measurement. Although neuroimaging demonstrates AD-related neurodegeneration, processing speed captures combined effects, comorbidities, and cognitive reserve, serving as an early marker for functional outcomes.

Among the studies that showed other tools for assessing preclinical stages of NCD that complemented cognitive neural vulnerability, there are studies that incorporate high-resolution electroencephalography measurements [52], olfactory markers [64], auditory [30], retinal thickness measurement by optical coherence tomography [64], use of ML algorithms for speech analysis [9], and home-based sleep studies from specific devices [17]. Some of these works were intended to assess preclinical stages of dementias other than AD, and in the review done by Khan et al in 2020 [9], the proposal of voice analysis in audios and videos allowed for this analysis in several languages. These studies suggest challenges with tests in English, requiring validation for diverse languages and contexts. However, they feature smaller populations, necessitate specific devices, and occur in nonclinical settings.

Literature on the use of VR for early diagnosis of preclinical NCD was limited, unlike its extensive use in cognitive skill training. Papers related to VR for diagnosis or treatment increased from 2008 to 2017, declined until 2020, then started rising again (Table 5).

By 2011, it was confirmed that ego and allocentric memory, linked to the parietal association cortex and medial temporal cortex, could serve as early markers of cognitive decline. VR models, like park or maze navigation, facilitated assessment [23]. Moreover, a Canadian team compared NC subjects with MCI patients using the Montreal Cognitive Assessment, Rivermead Behavioral Memory Test, and a VR test where subjects choose an apartment. The VR test correlated positively with the Montreal Cognitive Assessment, unlike traditional tests, but the sample size was small [39].

The study of Allain et al [24] compares cognitively healthy controls with patients with AD (varying stages, Mini Mental State Examination 18‐26 points) regarding functionality using a virtual coffee preparation task. Measures include completion time, achievement, and error scores compared with real-world tasks. With 24 patients with AD and 32 controls, the study demonstrates VR’s feasibility in studying AD deficits in ecologically valid environments, though limited to a single task.

In 2014, Tarnanas et al [65] conducted research correlating daily living activities assessment in virtual environments with biomarkers like neuropsychological tests, event-related potentials, and MRI. Their study, robust compared to others, suggests VR performance equals biomarkers, attributed to VR’s cognitive fidelity and rich behavioral data reflecting early-stage neurocognitive processes.

Zygiuris et al [56] introduced the virtual supermarket, a VR tool for rehabilitation and screening. The article extensively examined its validity with various measures and set cutoff points for a diagnostic algorithm. Several papers corroborate the apparent sensitivity of visuospatial functions in early NCD detection, evaluating ego and allocentric orientation. Morganti [21] compared a paper and VR version of Money’s “Road Map” test, noting the virtual version’s increased difficulty. They hypothesized that participants solve the traditional version through egocentric spatial transformations, while VR decisions are made based on on-screen interactions. This makes VR tools an interesting alternative, but one that needs to be carefully evaluated to determine what factors influence the results. Similarly, Mohammadi et al [20] used a VR navigation task to distinguish between monodomain and multidomain amnestic MCI, patients with AD, and normal controls, comparing results with traditional neuropsychological tests. They analyzed correct responses and response times in neighborhood and maze environments, establishing distinctive patterns in orientation (ego/allocentric) and visual/verbal memory.

Howett et al [57] published a study correlating entorhinal cortex volume measures, proposed as an early AD marker, with changes in immersive VR tests. They found consistent results with traditional neuropsychological tests, suggesting navigation tasks aid in early AD diagnosis [57]. Within this group, Lecouvey et al [59] utilized VR to evaluate prospective memory through tasks in a virtual city, comparing it with traditional neurocognitive measurements. Results confirmed early prospective memory alterations in AD, suggesting VR as a reliable assessment tool.

Turner’s team [37] created a tablet-based tool evaluating real-world task competence in a realistic VR setting, assessing cognition, motor skills, and self-reported cognitive abilities in patients with Parkinson disease.

To conclude, 2 articles in this review elaborated VR protocols to assess neurocognitive domains, revealing the progression from NC to MCI, focusing on memory and visuospatial functions. In 1 study, an Italian team devised a protocol to detect early cognitive signs of conversion in AD, focusing on egocentric and allocentric spatial representations. Previous studies showed alterations, especially in allocentric frames, in patients with amnesia with MCI and AD. Their innovation lies in proposing an intrinsic connection between egocentric/allocentric frames and spatial relations. The results revealed deficits in allocentric coordinated judgments, implying a deviation towards AD in the representation of metric distances [22]. In the other study, Machado et al [58] highlighted the use of VR environments, in particular 3D mazes, as diagnostic tools for MCI or dementia. Their study compares traditional methods with VR environments, combining precalibrated 3D tests with validated 2D neuropsychological assessments, allowing for assessment across several cognitive domains.

Finally, these studies, when paired with advanced AI algorithms, hold promise for early diagnosis. They enable cross-referencing of various variables, enhancing diagnostic accuracy [4,33,34,57,66].