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Current Alzheimer Research, XXXX, XX, 1-11 1
REVIEW ARTICLE

Artificial Intelligence in Eye Movements Analysis for Alzheimer’s Disease

Early Diagnosis
Shadi Farabi Maleki1, Milad Yousefi2, Navid Sobhi1, Ali Jafarizadeh1,*, Roohallah Alizadehsani3
and Juan Manuel Gorriz-Saez4,5

1
Nikookari Eye Center, Tabriz University of Medical Sciences, Tabriz, Iran;2Faculty of Mathematics, Statistics, and
Computer Sciences, University of Tabriz, Tabriz, Iran;3Institute for Intelligent Systems Research and Innovation,
Deakin University, VIC3216, Australia;4Department of Signal Theory, Networking and Communications, Universidad
de Granada, Granada, Spain;5Department of Psychiatry, University of Cambridge, Cambridge, UK.

ARTICLE HISTORY
Received: April 18, 2024
Revised: May 14, 2024
Accepted: May 16, 2024
DOI:
10.2174/0115672050322607240529075641
Abstract: As the world's population ages, Alzheimer's disease is currently the seventh most com-
mon cause of death globally; the burden is anticipated to increase, especially among middle-class
and elderly persons. Artificial intelligence-based algorithms that work well in hospital environ-
ments can be used to identify Alzheimer's disease. A number of databases were searched for En-
glish-language articles published up until March 1, 2024, that examined the relationships between
artificial intelligence techniques, eye movements, and Alzheimer's disease. A novel non-invasive
method called eye movement analysis may be able to reflect cognitive processes and identify ano-
malies in Alzheimer's disease. Artificial intelligence, particularly deep learning, and machine
learning, is required to enhance Alzheimer's disease detection using eye movement data. One sort
of deep learning technique that shows promise is convolutional neural networks, which need fur-
ther data for precise classification. Nonetheless, machine learning models showed a high degree of
accuracy in this context. Artificial intelligence-driven eye movement analysis holds promise for
enhancing clinical evaluations, enabling tailored treatment, and fostering the development of early
and precise Alzheimer's disease diagnosis. A combination of artificial intelligence-based systems
and eye movement analysis can provide a window for early and non-invasive diagnosis of
Alzheimer's disease. Despite ongoing difficulties with early Alzheimer's disease detection, this pre-
sents a novel strategy that may have consequences for clinical evaluations and customized medica-
tion to improve early and accurate diagnosis.

Keywords: Eye movements, Alzheimer's disease, artificial intelligence, neurodegenerative disease, geriatrics, machine learn-
ing, deep learning.

1. INTRODUCTION wing concern, ADRDs affect individuals in mid-life and es-

The aging of the world's population has led to a rise in
age-related noncommunicable diseases; Alzheimer's disease
(AD) stands out as the seventh leading cause of mortality
worldwide [1]. Projections suggest that the number of AD
cases could triple to 152 million by 2050 [2]. AD, responsi-
ble for 60-80% of dementia cases, is a progressive neurode-
generative disease marked by cognitive, behavioral, and
functional impairments [3]. AD pathology shows the build-
up of intracellular neurofibrillary tangles (NFTs) and extra-
cellular amyloid beta (Aβ) plaques [4, 5]. Public health and
healthcare systems need to tackle the challenges that are in-
creasing with the growing number of people with AD. The
burden of Alzheimer’s Disease and related dementias [A-
DRDs] is anticipated to rise rapidly with population aging,
particularly in low- and middle-income countries [6]. A gro-
* Address correspondence to this author at the Nikookari Eye Center,
Tabriz University of Medical Sciences, Tabriz, Iran;
E-mails: Jafarizadeha@tbzmed.ac.ir; Ali.jafarizadeh.md@gmail.com
1567-2050/XX $65.00+.00
calate in older adults, constituting a significant yet often
overlooked aspect of mental health burdens [7]. Modern sci-
ence is working to improve AD diagnosis techniques, look-
ing for quicker, less invasive ways with higher accuracy [8,
9].
Current methods for detecting AD, such as neuroimag-
ing and biomarkers, have limitations in terms of accuracy,
cost, availability, and ease of use. Neuroimaging techniques
such as positron emission tomography (PET) and magnetic
resonance imaging (MRI) are non-invasive and offer valu-
able insights into brain structure and function. However,
they can be costly and time-consuming [10]. Biomarkers,
such as cerebrospinal fluid (CSF) analysis, can help diag-
nose AD with greater accuracy, but they are invasive and
may not be accessible to all patients [11]. With artificial in-
telligence (AI) at the forefront of scientific advancement, tra-
ditional methods such as imaging (MRI) or computed tomog-
raphy (CT) and body fluid biomarkers (CSF) may not be
able to distinguish early-stage advances [12] adequately. To-
day, early diagnosis and secure screening tools are included
© XXXX Bentham Science Publishers
2 Current Alzheimer Research, XXXX, Vol. XX, No. XX
in these advancements [13]. Therefore, it is imperative that
eye movement (EM) data has been studied for decades and
has expanded its relevance to AD research by offering in-
sights into cognitive and memory states. Moreover, a study
has surfaced that examines new and safe screening and early
diagnosis instruments with AI methods [14].
With a nearly 70-year history, AI is a dynamic field
within computer science that develops systems effective at
process data, represent knowledge and promoting learning
[15, 16]. The progression of AI can be delineated through
three distinct generations. Initially, in the first generation, AI
primarily focused on rudimentary tasks [17]. Subsequently,
during the second generation, advancements led to the crea-
tion of autonomous software that can mimic human-like in-
telligence. Finally, in the third generation, AI systems are
poised to transcend human intellect, potentially achieving
self-awareness [17]. This evolutionary trajectory signifies a
remarkable advancement in the field of AI research and de-
velopment [17].
AI has the potential to assist healthcare professionals
with routine tasks, detection, and prescription decision-mak-
ing. It also raises important questions about how to improve
healthcare's efficiency, accuracy, and impartiality [18]. This
review explores AD detection, highlighting the importance
of early detection and going over the AI algorithm's capacity
to analyze eye movement data for AD detection. It provides
a thorough overview of the current state of Alzheimer's re-
search as well as its prospects going forward. It also investi-
gates the limitations of the diagnostic markers used today,
the possibilities of EM analysis, and the revolutionary role
of AI in enhancing diagnostic capabilities. AI algorithms,
widely successful in medical applications, play a key role in
detecting and diagnosing various diseases [19, 20].
2. LITERATURE SEARCH STRATEGY
The Cochrane Library, PubMed, Medline, Scopus, Goo-
gle Scholar, and SpringerLink are just a few of the academic
databases that were used to review recent literature. Only En-
glish-language publications were included in the study,
which made use of the most recent data available as of
March 1, 2024. The search phrases "Deep learning", "Ma-
chine Learning", "Artificial Intelligence", "Eye Movement-
s", "Eye Tracking", "Alzheimer's disease", and "Alzheimer--
type dementia’s" defined the keywords. This study aimed to
obtain a comprehensive and current understanding of the re-
lationships among eye movements, dementia, AD, and the
developing fields of deep learning (DL), machine learning
(ML), and AI.
3. DIAGNOSIS OF AD
Effective AD intervention requires early diagnosis and
ongoing observation [21]. Standard components of an AD di-
agnostic procedure include a physical examination and struc-
tural imaging using techniques such as MRI and CT scan
[22]. The primary purpose of these tests is to rule out other
conditions that may present with symptoms resembling
Farabi Maleki et al.
those of AD but require different forms of care [23]. Mea-
surements of CSF and other validated markers, like imaging
modalities, are presently quite accurate in diagnosing AD
[24]. While brain imaging and fluid biomarker analysis are
frequently employed, their utility is limited to specific sce-
narios due to challenges with specificity, invasiveness, and
impairments of various cognitive, motor, and perceptual pro-
cesses, such as working memory, learning, attention, motion
processing, and processing speed [1]. The ideal AD marker
should be non-invasive, simple, and affordable [25]. Bio-
markers like beta-amyloid and tau in CSF and brain, com-
bined with neuroimaging and immunological detection, of-
fer a promising path for diagnosis. Yet, challenges like high
cost and low sensitivity persist, and the relevance of specific
biomarkers to early and accurate AD detection remains de-
batable [26]. Therefore, there is a pressing need for alterna-
tive, accessible, and affordable methods with high sensitivi-
ty in AD detection.
AD diagnosis is difficult due to its ambiguity and multi-
faceted symptoms. However, recent findings indicate that an-
alyzing eye movements during visual exploration can reveal
insights into impaired cognitive processes [27]. Given the
shared neural and vascular characteristics between the eye
and the brain, eye movement assessment emerges as a
promising alternative to identify individuals at high risk for
AD [28]. Evaluating eye movements may be a promising al-
ternative method to identify individuals at high risk for AD,
offering language-independent and culture-fair measures of
various cognitive, motor, and perceptual processes such as
motion processing, attention, processing speed, inhibition,
working memory, and learning.
Saccades, the rapid eye movements that direct attention
toward visual stimuli, are fundamental to functional impair-
ments in patients with AD at mild to moderate stages and in
patients with amnestic mild cognitive impairment (MCI) re-
semble those in mild AD patients. Lage et al. [29] found that
prosaccade latencies exhibited the strongest correlations to
constructional and imitative praxis in the neuropsychologi-
cal assessment, suggesting that prosaccade latencies may be
affected by parietal damage in AD. Tokushige et al. [30]
found that patients with AD show longer latencies than the
control group in horizontal and vertical prosaccades and re-
turn saccades.
Antisaccade tasks inhibit eye movements in response to
stimuli and are associated with frontal lobe function. Dys-
function in antisaccade tasks indicates a significant insight
into neurological and psychiatric conditions, particularly in
AD [31]. Recent research highlights the significance of the
antisaccade task as a major abnormality in early AD com-
pared to healthy controls (HCs) [32]. A study by Kaufman et
al. [33] found that patients with AD and MCI had impaired
inhibitory control and error correction in antisaccades,
which exceeded the effects of normal aging and correlated
with dementia severity [34]. However, the task is difficult
for elderly patients, especially those with dementia. Another
study by Opwonya et al. [28] revealed that prosaccade and
antisaccade latencies and frequency of antisaccade errors
AI in Eye Movement Analysis for Alzheimer Alzheimer’s
show significant differences among patients with AD and
MCI.
Smooth pursuit tasks involve following moving targets
continuously [35]. These tasks are used to identify any im-
pairments in compensatory saccades and to measure factors
like latency and velocity, particularly in patients with AD
[36]. Prolonged latencies in smooth pursuit tasks are one of
the abnormalities that could be observed in AD. The poten-
tial mechanisms underlying smooth pursuit abnormalities in
AD may involve impairments in the neural networks respon-
sible for visual attention, motor control, and predictive mech-
anisms for smooth pursuit [36]. Specifically, abnormalities
in the basal ganglia, parietal lobe volume, and the integrity
of the predictor mechanism for smooth pursuit may con-
tribute to the observed deficits in smooth eye movement con-
trol in AD patients. Additionally, dysfunction in the accelera-
tion saturating nonlinear element that limits smooth pursuit
and the occurrence of large-amplitude saccadic intrusions
disrupting pursuit suggest complex interactions between cog-
nitive and motor processes in AD-related smooth pursuit ab-
normalities [37]. Fletcher et al. found that smooth pursuit
dysfunction is present in AD and is associated with impair-
ments in visual attention and motor control [37]. The study
also found that smooth pursuit dysfunction is not specific to
AD and can also be found in other neurological disorders,
such as Parkinson's disease. Another study reported that
smooth pursuit abnormalities, including decreased gain and
increased latency, are prevalent in AD and are associated
with impairments in visual attention and motor control [38].
These abnormalities have been found to be related to the de-
gree of cognitive impairment in AD patients.
Pupillary responses, affected by both the autonomic and
central nervous systems, show decreased amplitude, in-
creased latency, and decreased velocity in AD, which may
be related to cholinergic impairments in the visual system
[39]. Pupillary responses, saccades, and smooth pursuit are
just a few of the eye movements that AD notably affects
[40]. Microsaccades and saccadic intrusions, as well as tiny
eye movements made during fixation change in AD, may be
signs of cognitive decline [41]. Therefore, understanding th-
ese ocular alterations is crucial for assessing functional im-
pairment related to AD [42]. Fig. (1) shows the diverse
range of abnormal eye movements observed in AD.
Eye tracking (ET) is a simple, accurate, and non-inva-
sive screening tool that holds significant promise for AD di-
agnosis. These techniques measure eye position, movement,
and pupil size, detecting areas of user interest. Utilizing opti-
cal methods, especially infrared reflection, ET offers a sensi-
tive measure of cognitive impairment by examining explora-
tion patterns without explicit instructions [43].
Eye trackers have been used to measure gaze fixation
and saccadic motions for AD diagnosis in controlled lab sett-
ings. However, in real-world situations such as daily activi-
ties, computational video analysis is needed for more accu-
rate assessments [44]. Combining computer vision tech-
niques with insights from psychology and neurology helps
distinguish attention-grabbing elements in scenes. Analyz-
Current Alzheimer Research, XXXX, Vol. XX, No. XX 3
ing recorded videos in this way could aid in early detection
by comparing areas of interest in people with AD and those
without [45]. In general, data on eye movements falls into
three categories: ET data, webcam data, and gaze estimation
data from head-mounted devices [46]. Identifying abnormali-
ties in eye movements for early diagnosis of dementia in the
elderly is a scientific challenge. Some approaches aim to em-
ulate the human visual system, using computational models
like computational visual attention models (CVSM) on ego-
centric video to estimate areas likely to capture human visu-
al attention in naturalistic scenarios [47]. Early visual salien-
cy modeling used handcrafted low-level features, integrating
color, contrast, edges, and orientation based on Treisman
and Gelade's theory [48]. Many approaches added high-
er-level features like objects and faces. Recently, as AI has
become integrated into virtually every domain, the impact of
AI algorithms is noticeable in the analysis of eye move-
ments. Presently, eye movement data rank among the essen-
tial inputs for training AI models, specifically in the diagno-
sis of cognitive disorders such as AD [49]. So, the latest
studies focused on improving the precision, sensitivity, and
speed of these models to enable early diagnosis of AD and
other neurodegenerative disorders.
4. AI AND AD DETECTION USING EYE MOVE-
MENTS DATA
Similar to other fields, AI has rapidly advanced in aiding
humans in this realm and has provided new opportunities for
detecting various diseases with increased capabilities and
speed [50, 51].
4.1. ML Approaches
Initially, ML methods were applied in a variety of fields
of medical sciences, and their effective results have been re-
ported [49]. ML, known as a main branch of AI, uses certain
algorithms to let computers learn, decide, and predict things
without the need for explicit programming. It encompasses
developing algorithms that improve performance over time
by processing data [52, 53]. Contrary to traditional program-
ming, ML relies on examples, allowing computers to deter-
mine how to achieve goals based on given tasks. Voice assis-
tants, recommendation engines, self-driving cars, and predic-
tive analytics have all advanced thanks to their capacity to
learn from data. Lagun et al. applied ML to enhance MCI de-
tection, utilizing ML methods to model eye movement char-
acteristics like fixations, saccades, and re-fixations during
the Visual Paired Comparison task. Support Vector
Machines (SVMs), which were fed these features, distin-
guished between age-matched controls and MCI subjects
with 87% accuracy, 97% sensitivity, and 77% specificity by
combining SVMs with fixation and saccade patterns [54].
Various classifiers, such as Naïve Bayes, k-nearest neigh-
bor [KNN], decision trees, neural networks, and SVM, are
integral to classifying cognition status for AD detection
[55]. Naïve Bayes groups training instances based on dis-
tances using lazy learning, whereas KNN groups them based
on feature independence using the Bayes Theorem [55].
4 Current Alzheimer Research, XXXX, Vol. XX, No. XX
Fig. (1). Schematic illustration depicting various abnormal eye movements observed in AD. (A higher resolution / colour version of this fig-
ure is available in the electronic copy of the article).
Neural networks mimic the synaptic connections found in
the human brain, and decision trees use a branching struc-
ture. SVMs provide a variety of kernel functions, including
linear, non-linear, Radial Basis Function (RBF), polynomial,
Gaussian, and sigmoid, and they locate hyperplanes for class
separation by projecting data into higher dimensions. Never-
theless, there are difficulties in the field due to studies that
use unidentified kernels and a similar lack of specificity
when using neural networks, which can include deep multi-
layer perceptron (MLP), recurrent neural networks (RNN),
long short-term memory (LSTM), or convolutional neural
networks (CNN) [56].
Jang et al. presented an ML analysis of a new multimo-
dal dataset used for AD classification; they included it from
two previously unassessed tasks (describing a pleasing
former experience and pupil fixation) and two well-known
tasks (paragraph reading and picture description). The da-
taset, comprising eye movement and language data from 79
AD patients, subjective memory complaints (SMC), MCI,
and 83 older HCs, demonstrated similar classification accura-
cy for novel and established tasks. Combining data from all
tasks resulted in the highest total area under the curve
(AUC) of 0.83 ± 0.01, highlighting the complementary na-
ture of novel task data to well-known tasks [57].
Fraser et al. classified cognitive impairment more accu-
rately than neuropsychological tests by using eye tracking,
speech, and comprehension measures. When compared to
neuropsychological tests and an early fusion approach, multi-
modal data from language tasks demonstrated superior re-
sults at the task level (AUC = 0.88, accuracy = 0.83) in a
Farabi Maleki et al.
study involving 26 MCI participants and 29 controls using a
multimodal ML approach. Combining language and neu-
ropsychological classifier predictions improved results
(AUC = 0.90, accuracy = 0.84), with language predictions
moderately correlating with Rey Auditory Verbal Learning
Test scores. Performance and interpretability are improved
by this modular strategy, which can be adjusted to different
classifiers and data sources [58]. Comparably, Barral et al.
demonstrated that speech and ET data combined yield better
AD classification via ML algorithm than either modality
alone. In experiments with 68 memory clinic patients and 73
healthy volunteers, ET alone. Predicted AD (AUC = 0.73)
and the combined approach achieved the best classification
performance (AUC = 0.80) [59].
In an international study, dual-task patterns, eye move-
ment, and gait were assessed in 1,481 participants (724 cog-
nitive impairment, 757 controls) by Lin et al. Out of 105 fea-
tures extracted with LightGBM, 46 parameters showed signi-
ficant group differences (P < 0.05), with 32 of them related
to gait and 14 to ET. A significant correlation was observed
between plasma p-tau181 levels and dual-task cost-Turn
Time and Gait_3Back-TurnTime. A model that combined
prosaccade, antisaccade, dual- task smooth pursuit, and du-
al-task gait yielded a high AUC rate of 0.987 for cognitive
impairment detection. When joined with p-tau181, the mod-
el's AUC of 0.824 aided in its ability to differentiate MCI
from controls [60].
ML techniques frequently map facial landmarks to the
point of gaze, which facilitates the task when the head is mo-
tionless. However, the transformation becomes more com-
AI in Eye Movement Analysis for Alzheimer Alzheimer’s
plex and specific to the head position when it changes. ML
can estimate these intricate relationships, but current open-
source methods do not achieve the accuracy required for psy-
chophysics experiments (>3 degrees of visual angle) [61].
Kim et al. carried out a study to find key behavioral traits
from a virtual kiosk test in order to differentiate MCI pa-
tients from HCs and develop an ML model for early screen-
ing. Fifty-one participants were enrolled in the virtual kiosk
test, which tracked their hand and eye movements and com-
puted four behavioral features. Statistical analysis revealed
significant differences in fixation duration, time to comple-
tion, hand movement speed, and number of errors among
MCI patients and HCs. Analyzing eye and hand movements
during the virtual kiosk test, an SVM model demonstrated
notable potential for early MCI screening, with an accuracy
of 93.3%. The mentioned digital marker in virtual reality is
a useful tool for early MCI screening because, in contrast to
traditional biomarkers, it allows ecologically usable data col-
lection at a reasonable cost in a short amount of time [62].
ML has thus demonstrated its potential for helping the
healthcare system, particularly with regard to AD detection.
Different ML classifiers, such as Naïve Bayes, KNN, deci-
sion trees, neural networks, and SVM, are needed to classify
cognitive status in AD diagnosis despite challenges like low
neural network specificity and undefined kernels. By demon-
strating how ML can be used to reliably and early detect cog-
nitive impairment by using a variety of data sources, these
advancements will heighten the field's significance and
progress.
4.2. DL Approaches
With the spread of AI methods around the world and net-
works being used, newer methods such as DL have come to
the fore and have revolutionized the healthcare system [63,
64]. Generally, DL, particularly CNN, showed promise but
required more annotated data. There are two main categories
in DL: bottom-up, which uses features like color and con-
trast, and top-down, which requires prior knowledge. Cur-
rently, most work falls under bottom-up methods. For ins-
tance, a study by Sun et al. applied ML and DL models to
identify key eye movement features in AD during a 3D visu-
ospatial memory task. The novel DL model, incorporating a
nested autoencoder network and a weight adaptive network
layer, achieves an average accuracy of 85% in distinguish-
ing patients with AD from HCs [65].
Jiang et al. established an automatic MCI detection ap-
proach, employing multimodal measurements and the Deep
Belief Network (DBN) framework for primary cognitive as-
sessments in clinical practice. Studying 152 MCI patients
and 184 HCs, they used Electroencephalogram (EEG), eye
movement signals, and neuropsychological assessments. Af-
ter extracting features from physiological signals and apply-
ing a DBN framework, three models were constructed. The
combined model, integrating clinical variables, neuropsycho-
logical, and physiological features, showed superior MCI de-
tection accuracy (89.87%) compared to the feature model
(84.21%) and clinical cognitive model (73.52%) [66].
Current Alzheimer Research, XXXX, Vol. XX, No. XX 5
Similarly, Biondi et al. developed a DL approach to
distinguish eye movement behavior in people with neurode-
generative diseases through reading from HCs. Using ET da-
ta from people with and without AD reading various sen-
tences, their model, with denoising sparse-autoencoders and
a softmax classifier, achieved 89.78% accuracy in identify-
ing AD subjects [67]. Additionally, Harisinghani et al. ex-
plored ET data from a webcam using a DL approach. They
found that while the webcam gaze classifier is not as effec-
tive as high-end ET classifiers, it outperforms the majority--
class baseline in an area under the receiver operating charac-
teristic (AU-ROC). While there is still a long way to go be-
fore webcam gaze tracking is practically relevant for AD de-
tection, these results provide an encouraging proof of con-
cept and point to the need for more research into this technol-
ogy as a less expensive substitute for expensive eye trackers
[68].
Zuo et al. carried out a study focusing on utilizing DL to
diagnose AD through ET behaviors, emphasizing the clini-
cal value of visual attention. They collect heatmaps to ana-
lyze differences in visual attention between AD patients and
normal people by conducting a 3D visual task with a non-in-
vasive ET system. Introducing the Multi-layered Compari-
son Convolutional Neural Network (MC-CNN), they effi-
ciently distinguish visual attention disparities. MC-CNN's hi-
erarchical convolutional layers capture multi-layered
heatmap representations integrated into a distance vector for
improved task performance. Extensive experiments on their
dataset validate MC-CNN's consistent accuracy in classify-
ing AD patients and normal people based on ET data [69].
In an investigation by Haque et al., they created the Visu-
ospatial Memory ET Test (VisMET), a brief task identifying
cognitive impairment in AD in under five minutes. They im-
plemented the test on iPads to increase accessibility and
made a mobile version for broader use. Using transfer learn-
ing (TL), a DNN tracked eye gaze to extract memory fea-
tures for assessing cognitive status in a sample of 250 indivi-
duals. With a minimum ET calibration error of 2 cm, the
AUC of the test in identifying mild to severe cognitive im-
pairment increased to 0.76%, matching that of commercial
ET hardware. This study concludes with the presentation of
a mobile VisMET version that can effectively estimate the
presence of cognitive impairment [70].
The accuracy of multimodal AD detection can be im-
proved by integrating physiological signals such as heart
rate (HR), electrocardiography (ECG), and electromyogra-
phy (EMG) with ET [71]. EEG and ET are frequently used
together, but there is always potential for improvement, par-
ticularly when EMG or ECG features are integrated with ET
data to increase overall performance [72]. Studies frequently
fail to take inter- and intra-subject variability into account.
Retraining for new users may be necessary due to high
recognition rates that are limited to intra-subject classifica-
tion [73]. Conversely, a method that works well for classify-
ing different subjects can be applied to different users with-
out requiring retraining [57]. Further studies on ET imple-
mentation are necessary, particularly with regard to smart-
6 Current Alzheimer Research, XXXX, Vol. XX, No. XX Farabi Maleki et al.

phone cameras that use CNNs. Smartphone cameras can ex-
tract relevant ET features. Additionally, integrating ET and
cognitive assessment technologies for AD detection could
have a significant positive impact on applications such as
meditation, advanced driving assistance systems (ADAS),
and smart homes [74].
Digital biomarkers linked to pupillary reflexes and eye
movements are collected using cameras and light sensors,
which are widely used in research and disease diagnosis
[75]. Patients with AD have been shown to exhibit early ab-
normalities in their eye movements [55]. Eye-hand tasks are
used to evaluate dysfunctions of the visuomotor network,
which may be biomarkers of AD and MCI. Research using
low-cost robotic interfaces like the Omni robot and ET de-
vices like the Gazefinder NP-100 show promise in differenti-
ating between cognitive and motor behavior impairments in
AD patients [76]. Innovations such as wearable sen-
sor-based glasses, termed NeuroGlasses, offer the potential
to discern disparities in visual attention patterns between in-
dividuals with AD and those without the condition [77]. By
utilizing DL, cutting-edge technologies like MC-CNN and
DeTrAs demonstrate the potential for individualized support
within a patient-centered healthcare system, enhancing the
clinical assessment of early dementia [77]. Table 1 provides
an overview of recent studies that explored AI algorithms in
ET data for AD detection. Fig. (2) depicts the eye tracking
process for identifying abnormal eye movements in AD, inte-
grated with AI analysis for diagnostic purposes.

Fig. (2). Overview of the eye tracking process for identifying abnormal eye movements in AD, integrated with AI analysis for diagnostic pur-
poses. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
AI in Eye Movement Analysis for Alzheimer Alzheimer’s Current Alzheimer Research, XXXX, Vol. XX, No. XX 7

Table 1. A brief assessment of existing research that used AI for eye movement analysis and AD diagnosis.

Author Year Data Sample AI-Model Tasks Findings

The algorithm achieved 87% accuracy, 97%
Distinguishing age-matched con-
Lagun et al. [54] 2011 Eye movements data SVM sensitivity, 77% specificity, and AUC of
trols from MCI subjects
0.869
DL (softmax clas-
Biondi et al. [67] 2018 ETdata Classification (AD and HCs) Achieved 89.78% of accuracy
sifier)
Multimodal data [ECG, neu- Deep Belief Net-
Classification (MCI, healthy The combined model reached an accuracy
Jiang et al. [66] 2019 ropsychological assessments, work Framework
adults) of 89.87%
and eye movements] [DBN]
Cognitive impairment classifica- Combining language and neuropsychologi-
eye tracking, speech, and com-
Fraser et al. [58] 2019 LR, SVM tion, outperforming neuropsycho- cal classifiers reached the highest perfor-
prehension measures
logical tests mance (AUC = 0.90, accuracy = 0.84)
LR, RF, and Combining ET and speech data Multimodal data reached the best classifica-
Barral et al. [59] 2020 eye tracking, and speech data
GNB for AD classification tion performance (AUC = 0.80)
multimodal dataset of language LR, RF, and Classification (MCI, healthy
Jang et al. [57] 2021 Reached the highest overall AUC of 0.83
and eye movements GNB adults)
Visuospatial Memory ETTest
Haque et al. [70] 2021 DNN and TL Classification (AD and HCs) (AUC of 0.76)
[VisMET]
ML combined The combined model achieved 85% of accu-
Sun et al. [65] 2022 ETdataset Classification (AD and HCs)
DL racy and 0.977 of AUC
Classification (MCI, healthy The SVM model achieved 93.3% accuracy
Kim et al. [62] 2023 Eye movement data SVM
adults) and an AUC of 0.98
Zuo et al. [69] 2023 ETdata MC-CNN Classification (AD and HCs) Achieved the highest accuracy of 0.83
Harisinghani et al. the webcam gaze classifier isn't as effective
2023 ET data from the webcam DL Classification (AD and HCs)
[68] as high-end ETclassifiers
A model based on dual-task smooth pursuit,
gait, eye movements, and dual--
Lin et al. [60] 2024 LightGBM Classification (CI, controls) dual-task gait, antisaccade, and prosaccade
task patterns
achieved the best AUC of 0.987

4.3. Explainable AI (xAI)
Researchers are now concentrating on AI system
progress in an effort to detect AD earlier. However, the poor
transparency and interpretability of these models have limit-
ed their usefulness in clinical settings. This brings us to xAI,
a subfield of AI devoted to building transparent and compre-
hensible models that can make their decision-making pro-
cesses more understandable to humans. This is particularly
crucial because traditional AI models are often difficult to in-
terpret due to their complexity, which diminishes their relia-
bility [78]. xAI becomes a major factor in improving model
interpretability by using data from non-invasive methods, es-
pecially through feature selection. Choosing the best fea-
tures for a model requires determining which features are
most important, ranking them, minimizing overfitting, and
exposing any biases by combining multiple feature selection
techniques to find dominant features in a sizable dataset
[79]. The study discusses the promise of xAI and helps with
the early diagnosis of AD [80]. Feature selection is a critical
xAI technique that gives ML models transparency and inter-
pretability, which in turn builds trust and improves decision-
making in AD prediction [81].
normal individuals may show results outside of the normal
range, complicating early diagnosis of AD [82].
Due to the limitations of current ET system functions
and algorithms in 3D displays, the majority of experimental
stimuli have been presented in two dimensions in most
studies. Prediction, detection, prognosis, and decline mea-
surement are important issues in addressing AI challenges in
dementia-related research. The ‘‘oblack-box’’ nature of AI
creates challenges for accountability and complicates clini-
cal trust and decision-making authority. Because algorithms
trained on biased datasets affect diverse populations differ-
ently, problems with population generalizability and data
equity arise [83]. Marginal gains over established factors
like age and sex, covariance among risk factors, and small
sample sizes are some of the challenges that ML faces. Inter-
pretability issues at the population level raise doubts about
the causal relationship between the risk factors that are high-
lighted, accounting for elements such as a broadly applica-
ble ‘‘protective lifestyle’’ [84]. These problems are made
worse by participation and attrition bias, which makes meth-
ods like participation weights necessary for mitigation. Gain-
ing trust in the individual-level clinical applications of mod-
eling requires an understanding of these limitations [85].

5. CHALLENGES AND LIMITATIONS There are two primary problems with webcam ET tech-
nology as it stands today: it has a number of severe limita-
The existing eye movement tests are helpful, but they tions, which makes it challenging to diagnose AD by using
have limitations because, as people age, even cognitively AI in ET data. First and foremost, no fixation detection algo-
8 Current Alzheimer Research, XXXX, Vol. XX, No. XX Farabi Maleki et al.

rithm has been developed, especially for low-frequency web- LIST OF ABBREVIATIONS
cam data. This limitation potentially compromises the validi-
ty of the results by adding another level of complexity to the AD = Alzheimer's Disease
eye movement isolation procedure. Some novel techniques ADAS = Advanced Driving Assistance Systems
aim to circumvent this limitation in order to provide more re-
liable insights into the patterns of eye movement associated ADRDs = Alzheimer's Disease and Related Dementias
with AD [65]. Secondly, there is no algorithmic support for AI = Artificial Intelligence
taking head movements into account when predicting gaze
points. Because these online experiments are inherently un- AUC = Area Under the Curve
supervised, it is impossible to guarantee that participants AU-ROC = Area Under the Receiver Operating Charac-
will maintain a stationary head position, even in the face of teristic
clear instructions. The diagnostic predictions may become
less accurate as a result of this variability, which adds a Aβ = Amyloid Beta
large confounding factor [86]. Thus, although AI has great CNN = Convolutional Neural Networks
potential to diagnose AD using ET data, there are currently
significant obstacles, such as the inability to detect fixation CSF = Cerebrospinal Fluid
in low-frequency webcam data and the lack of support for CVSM = Computational Visual Attention Models
head movements. However, new technologies are emerging
on a daily basis to address the issues above, including en- CT = Computed Tomography
hanced webcam data, advanced fixation detection, head DBN = Deep Belief Network
movement integration, remote eye tracking devices, sensor
fusion, and real-time feedback [87, 88]. DL = Deep Learning
ECG = Electrocardiography
CONCLUSION
EEG = Electroencephalogram
Conclusively, lacking precise and non-invasive biomark-
ers for Alzheimer's Disease and related dementias (ADRDs) EMG = Electromyography
necessitates the development of novel diagnostic strategies,
ET = Eye Tracking
especially for early detection, given the increasing global
prevalence of ADRD. The older methods, such as imaging HCs = Healthy Controls
and fluid biomarkers, face limitations in terms of invasive-
HR = Heart Rate
ness, specificity, and cost. The primary focus of this fascinat-
ing field of research on how eye movements reflect cogni- KNN = k-nearest Neighbor
tive processes is analysis using AI algorithms. Advances in
LSTM = Long Short-term Memory
diagnostic capabilities are required due to the complexity of
AD diagnosis, and AI shows great promise, having grown MC-CNN = Multi-layered Comparison Convolutional
over decades. This study discusses the restrictions of the Neural Network
available diagnostic approaches while exploring the revolu-
tionary potential of AI in the analysis of eye movement data MCI = Mild Cognitive Impairment
for AD detection. Integration of ML and DL techniques in ML = Machine Learning
AD detection with eye movement data shows notable
achievements in terms of classification accuracy. DL mod- MLP = Multilayer Perceptron
els, which include CNNs and ML classifiers like SVM, RF, MRI = Magnetic Resonance Imaging
DT, etc., yielded their ability to discriminate between AD pa-
tients and HCs. Multimodal datasets, which incorporate ET NFTs = Neurofibrillary Tangles
with additional measures, can help improve accuracy fur- PET = Positron Emission Tomography
ther. In clinical settings, models' dependability, transparen-
cy, and interpretability become vital requirements for xAI. RBF = Radial Basis Function
Despite these developments, there are still problems. These RNN = Recurrent Neural Networks
include algorithmic constraints on 3D displays as well as
problems with data equity, population generalizability, and SMC = Subjective Memory Complaints
interpretability. These problems must be resolved for AI to SVM = Support Vector Machines
be used effectively in the early diagnosis of AD. Undertak-
ing such efforts could result in improved clinical evaluation TL = Transfer Learning
and tailored treatment in patient-centered healthcare sys- VisMET = Visuospatial Memory ET Test
tems.
xAI = Explainable AI
AUTHORS’ CONTRIBUTIONS
???????????????
AI in Eye Movement Analysis for Alzheimer Alzheimer’s
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
Juan Manuel Gorriz Saez is the EIC of the journal CAR.
ACKNOWLEDGEMENTS
Declared none.
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