Visuospatial navigation: an emerging biomarker for Mild Cognitive Impairment and AD disease

A Narrative Review

Abstract

Current neuroimaging and biomarker research is strongly focused on identifying individuals at high risk of developing dementia. In contrast, cognitive markers for early stage of Alzheimer’s disease are virtually non-existent, as diagnostics tool and outcomes measures remain centered on episodic memory deficits despite their low sensitivity and specificity for identifying at-risk individuals. Nowadays, however, emphasis is being placed on spatial symptoms in the genesis of AD. Spatial navigation -the ability to estimate one’s position based on environmental and self-motion cues- tends to decline with age, and this impairment is even more pronounced in Alzheimer’s disease (AD) or in mild cognitive impairment (MCI). This review highlights a novel approach of cognitive evaluation for early-stage AD, emphasizing how visual perception, visuo-constructional abilities and spatial navigation are increasingly shown to be present in at-risk individuals. Additionally, the review identifies key and research gaps and future research priorities in this area.

Keywords: Spatial Navigation, biomarkers, MCI, Alzheimer’s disease, Visuospatial abilities.

Introduction

Physiological aging is associated with structural and functional cerebral changes that may cause a mild decline in attention, executive functions, working memory and free memory recall. In the last decades, the number of subjects developing neurodegenerative disease, leading gradually to dementia syndrome-most commonly Alzheimer’s disease (AD)- has been increasing. According to current conceptualization, AD progresses in stages from a preclinical phase to mild cognitive impairment (MCI) to symptomatic AD (Rodrigues et al, 2019). Mild Cognitive impairment is a “transitional zone” between normal and pathological aging, referring to old individuals with some cognitive impairment due to a very slight degree of functional impairment (Rusconi et al, 2015). Therefore, early diagnosis, and identification of predictors of dementia in a pre-clinical phase are of critical importance in the elderly population. In recent years, several biomarkers associated with neuropathological processes have been identified.

Research indicates that reduced cerebrospinal fluid (CSF) levels of A42 reflect the aggregation of amyloid into plaques in the brain at autopsy and in vivo. Fibrillar amyloid- deposition can be detected through positron emission tomography (PET) studies using radiotracers such as Pittsburgh compound-B (PIB) with plaque formation indicated by higher uptake of the radiotracer. Thus, early detection of MCI is crucial for intervention and management. Current outcomes measures are still focused on episodic memory deficits despite their low sensitivity. The reliance on episodic memory deficits for diagnosis in the prodromal or even preclinical stages is problematic because episodic memory peaks in early adulthood and progressively declines with normal ageing. So, highlighting the potential difficulties with the sensitivity of episodic memory to diagnose and predicting AD pathophysiology in an older population (Coughlan et al, 2018).

Visuospatial cognition covers a wide range of non-verbal cognitive abilities that are pivotal for enabling individuals to interact with the environment effectively and are strongly linked to drawing and assembling (visuoconstructional) activities. This link is evident both in childhood, when the progressive maturation of visuospatial cognition parallels changes in performance on spatial construction tasks and in adulthood, when visuospatial deficits and disorders of spatial construction are frequently observed together following brain damage (Zappullo et al, 2025). Importantly, spatial navigation deficit may serve as early indicators of AD pathophysiology, as the brain regions first affected by AD are integral to AD the spatial navigation network. Genetically at-risk individuals show altered spatial navigation patterns before the onset episodic memory symptom. Thus, spatial navigation is emerging as a potential cost-effective cognitive biomarker to detect AD in the preclinical stages, which has important implications for future diagnostics approaches.

This review critically examines the potential of spatial navigation as a biomarker for MCI and its utility in distinguishing individuals who may progress to AD. Will discuss the contributions of several key studies to this emerging field, focusing on real-world and virtual navigation tasks, visuospatial perception, and the neural underpinnings of spatial deficits in MCI and AD.

Methods

A literature search was conducted using PubMed and Google Scholar to identify studies from the past 15 years that investigated spatial navigation deficits in individuals with MCI or dementia. Search terms included “spatial navigation”, “MCI”, “Alzheimer’s disease”, “dementia”, and “biomarkers”. Only human studies were considered, with a focus on clinical and neuropsychological assessment, as well as neuroimaging studies. These studies encompass a range of methodologies, including systematic reviews, clinical trials, neuroimaging research, and virtual navigation experiments. Studies where the full text was not available or where the abstract lacked basic information for review were removed. Additionally, non-English papers, meeting abstracts, conference proceedings, notes, case reports and editorial materials were not included.

Discussion

Visual perception

Recent neurophysiological and imaging studies have revealed that changes in visuospatial perception (VSP) functions can be detected in the early stages of Alzheimer’s disease. VSP refers to the cognitive process that entails the extraction and interpretation of spatial information from visual stimuli primarily mediated by the striate and extra striate regions. In their review Mandal and colleagues (2012) discuss visuospatial perception as an emerging biomarker for AD, emphasizing its neural correlates and the association between spatial deficits and AD-related brain changes.

Monitoring VSP functional networks in AD using fMRI can aid in the identification of the activation changes within these networks due to AD pathology and other disorders. For example, while visuospatial deficits are characteristic of both AD and Huntington’s disease, the specific components affected differ. In AD, patients show impairments in visuoconstructional tests requiring extra-personal orientation (e.g., copying a complex figure) whereas patients with Huntington’s performed poorly on visuospatial tasks requiring personal orientation (e.g., the Money Road Map Test requiring egocentric mental rotation in space) (Mandal et al, 2012). In summary, VSP deficits are prominent in AD and can be detected at the earliest prodromal stages. Assessing visuospatial perception, alongside the other cognitive domains affected in AD-such as episodic and semantic memory-may facilitate earlier detection of AD and enhance the accuracy by differentiating AD and other dementias.

Visuoconstructional abilities

Visuoconstructive abilities are considered part of visuospatial functions and refer to the ability of joining parts for producing two- or three-dimensional models both graphomotor (drawing) and non-graphomotor (building and assembling) activities. Despite their clinical relevance, certain types of two-dimensional and especially three-dimensional construction task, have been scarcely considered in the assessment of visuoconstrucional abilities. In their study, Rodrigues et al. (2019) aimed to investigate whether different types of visuoconstructional tasks (Clock Drawing Test, CDT; Block Design, BD; Visual Puzzles, VP three-dimensional Block Construction TBC) different in terms of complexity (number of dimensions and familiarity level) and skills required for execution (graphomotor vs non-graphomotor are useful to differentiate mild cognitive impairment (MCI) and early Alzheimer’s disease (AD) form cognitively normal older adults. The findings indicate that non-graphomotor visuoconstructional tasks are already impaired in the early stages of AD but are preserved in MCI individuals when compared with HCs. In conclusion, these results underscore the importance of considering task complexity (in terms of dimensionality and familiarity) and response modality (graphomotor vs. non-graphomotor) when assessing cognitive impairment in older adults

Spatial Navigation

Spatial navigation deficits have been increasingly recognized as an important early cognitive marker for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Spatial navigation refers to the process of determining and maintaining a trajectory between different points in the environment. Based on a reference point, (i.e. the origin), individuals may use two reference frames for organizing spatial information in memory coding: the allocentric and the egocentric frames. In an egocentric reference frame spatial locations are represented relative to the individual’s own position and orientation (subject-to-object relations) maintaining the same perspective in which the spatial information was acquired. In contrast, in an allocentric reference frame, involved by object-to-object relations, in which spatial locations are encoded independently of the individual’s orientation (object-centered) (Coughlan et al, 2018). Advances in the field have shown that broad network of brain regions underlies spatial navigation. These include medial temporal lobe (MTL) regions (Hippocampus, entorhinal cortex and parahippocampal cortex) parietal lobe regions (posterior cingulate, precuneus and retrosplenial cortex (RSC), frontal lobe regions and other subcortical structures (caudate nucleus and thalamus) underlies our ability (Coughlan et al, 2018).

Allocentric navigation is believed to be mediated by highly selective neuronal populations known as ‘place cells’ found in the CA1 and CA3 regions of hippocampus. These cells contribute to the formation of cognitive maps of the environment, providing local information about one’s location within that environment. On the other hand, large-scale spatial information is provided by grid cells located primarily in the medial entorhinal cortex, which can encode grid-like representations of distinct positions in space (self-location) and calculate routes between locations. Grid cells represent a core component of the neural system that underlies path integration as they also seem to measure distance travelled akin to an odometer. Additionally, head direction cells (which were first identified in the post subiculum of the rat) encode orientation in space and are activated whenever one is facing a certain direction (the reference direction) (Tuena et al, 2020).

This neuroanatomical and functional evidence supports the hypothesis that in the early stages of AD, brain regions that are primarily affected are those involved in the neural circuit that supports the processing of allocentric and egocentric representations, and their mutual relations. For instance, hippocampal damage impairs the construction and storage of a long term allocentric-map. On the other hand, the neurodegeneration of the restrosplenial cortex (RSC) seriously influences the allocentric-to-egocentric transformation which could result in an impoverished egocentric representation useful for navigation that could result from that process (Serino et al, 2014). As a result, many studies aimed at investigating the role of spatial navigation to distinguish mild cognitive impairment (MCI) from AD.

Spatial navigation as a diagnostic tool

Although growing evidence suggests that spatial navigation was impaired in early AD, its integrity in MCI or preclinical populations remains less well understood. The heterogeneity of this clinical condition has prevented us from reaching a consensus about its diagnosis. In fact, MCI could differ for type of cognitive domain impaired (aMCI versus non amnestic; naMCI), the quantity of domains compromised (single versus multiple domains) and the etiology (e.g., neurodegenerative, cerebrovascular, depression/neuropsychiatric) With respect to spatial navigation, several studies have reported impairments in both allocentric and egocentric frame and in the ability to switch between them in MCI (Tuena et al, 2020). Iachini et al, (2025) by adopting a dynamic spatial memory task (dyads of 3D geometrical objects) explored how the ì temporal order of item presentation influences egocentric and allocentric spatial judgments in individuals with early-stage Alzheimer’s disease (eAD) and healthy elderly individuals (normal controls—NC).

Results revealed that the temporal order affected spatial judgments in eAD patients but not in NC patients. This is presumably because eAD patients struggle to update spatial representations in dynamic situations. Their longitudinal study, Levine et al (2019) examined whether tasks assessing the ability to form, retain, and use a cognitive map or the ability to learn and retrieve a novel route predicted clinical progression. Cognitive mapping (CM) was assessed in 95 participants and route learning (RL) was assessed in 65 participants at baseline. Clinical progression over an average of 4 to 5 years was assessed using the clinical dementia rating (CDR) scale. The results emphasized CM was better than episodic memory in discriminating progression to symptomatic AD.

Additionally, current research investigating the use of developed virtual reality of spatial cognition has proved more sensitive in identifying spatial navigation deficits in patient populations. In particular, virtual reality testing can be applied as an alternative to real-world reality tests (which are difficult to administer with space constraints in clinical settings) to measure navigational abilities in younger and older age groups and in patients with MCI and early AD. Its potential relies on the capability to adapt and tailor environments according to patient’s and task’s needs, for example by changing or eliminating landmarks or pathways in spatial memory tasks. In their investigation, Allison et al. (2016) found that deficits in spatial navigation deficits could be detectable even in preclinical AD, before the onset of significant memory impairments. Using wayfinding and route learning in virtual reality environment compared to three groups: Clinically normal without preclinical AD, clinically normal with preclinical AD and early-stage symptomatic AD. The preclinical AD was defined based on cerebrospinal fluid A42 levels below 500 pg/ml (CN biomarkers +).

The results confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting cognitive deficits of AD. More, Laczo et al, (2022) in their study, using the Navigation test Suite (consist of tree navigation task: route-repetition, route retracing and directional-approach tasks) for investigating the differences in spatial navigation performance between participants with AD a-MCI, non-AD a-MCI, mild AD dementia and CN (cognitively normal older adults) and the associations of spatial navigation performance with MRI measures of atrophy in the specific MTL, cortical and subcortical regions. The results showed that in route learning, AD aMCI performed worse than non-AD aMCI who performed similarly to CN. In way finding, aMCI participants performed worse than CN and AD aMCI performed worse than non-AD aMCI in the second task session. In perspective taking/wayfinding, aMCI participants performed worse than CN AD aMCI and non-AD aMCI did not differ in cognitive tests. AD biomarker positive and negative older adults with aMCI had different profiles of spatial navigation deficits that were associated with posterior MTL and parietal atrophy and reflected AD pathology.

These studies have shown that spatial navigation is a promoter feature for AD, but for another disorder it is not well defined. Tu et al (2015) using virtual supermarket, compared performance on spatial orientation task with visual and verbal memory function with dementia patients and healthy controls. Spatial orientation performance was found to discriminate against AD and FTD (frontotemporal dementia syndromes). These findings confirm that impaired orientation is a prominent feature that can be applied clinically to discriminate between AD and FTD and that the retrosplenial cortex emerges as a critical biomarker to assess spatial orientation deficits in these neurodegenerative conditions.

However, despite clear clinical applications of the research, spatial navigation has several limitations as a diagnostic tool for AD. Importantly, spatial navigation studies in AD might be limited in comparability, as many of the studies predate the publication of robust diagnostic criteria for AD. The current lack of epidemiological data from healthy populations for spatial navigation is a further obstacle. Interindividual differences in spatial navigation remain elusive, with no population-level data available to rectify conflicting ideas around, for example, sex differences in navigational abilities. Another important limitation is related to the focus on Alzheimer’s. Most studies on spatial navigation concern AD, there are still very few studies on other forms of dementia such as Parkinson’s, Lewy Bodies. Limitations of current spatial memory research in MCI could be summarized in the need to consider different MCI typologies and dementia, also improve the VR tasks, including idiothetic cues, full-immersive solutions with comparison with real versions

Conclusion

This review underscores the presence of spatial navigation impairments in early AD and its prodromal and preclinical forms. The evidence reviewed clearly highlights the great potential of spatial navigation and orientation deficits as diagnostic measures and predictors of incipient AD pathophysiology. Specifically, the literature indicates that spatial navigation deficits can identify individuals at risk of developing AD, which has obvious implications for clinical practice. Nevertheless, the importance is still underestimated of spatial memory assessment in diagnosing and tracking AD. Spatial navigation represents an emerging biomarker that could help identify and monitor the onset of dementia and MCI with important implications for defining intervention strategies aimed at with beneficial implications for both AD patients and their caregivers.

Elena Piscopo

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BFJ BrainFactor Journal Num. 17 Vol. 1