1. Introduction
Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are among the most common forms of dementia, both profoundly impairing cognitive and behavioral abilities. AD typically affects both amnestic (learning and memory) and non-amnestic domains (executive function and visuospatial abilities), whereas FTD more often disrupts interpersonal conduct and self-regulation [
1,
2]. Clinically, however, differentiating AD from FTD remains challenging. Both disorders show overlapping patterns of neurodegeneration in the dorsolateral prefrontal cortex and medial temporal lobes, including the amygdala and hippocampus, and behavioral symptoms may overlap, particularly between the behavioral variant of FTD (bvFTD) or primary progressive aphasia and atypical AD [
3,
4]. Although MRI and biomarker assays such as cerebrospinal fluid (CSF) and positron emission tomography (PET) can aid diagnosis, these methods are costly, invasive, and limited in terms of temporal resolution and early detection abilities.
Electroencephalography (EEG) offers a cost-effective, noninvasive, and widely accessible alternative for assessing brain function. Conventional EEG analyses typically focus on spectral power or functional connectivity, but these approaches have limitations. Functional connectivity shows poor test–retest reliability [
5], while spectral analyses are confounded by baseline correction issues and broadband activity [
6].
In recent years, EEG microstate analysis has emerged as a promising approach to characterizing large-scale brain dynamics during rest [
7]. Microstates are quasi-stable scalp potential configurations lasting tens of milliseconds before rapidly transitioning, thought to reflect the sequential activation of large-scale neural networks [
8]. Canonical microstates (A–D) are associated with distinct topographies, temporal features, and putative cognitive functions (e.g., microstate A is linked to phonological processing, microstate B to the visual network, microstate C to the salience network, and microstate D to attentional networks) [
9]. Importantly, microstate parameters such as duration, occurrence, and coverage demonstrate high test–retest reliability across sessions, montages, and clustering procedures, underscoring their potential as biomarkers [
10].
Several studies have examined EEG microstates in AD and FTD. For example, one study reported a shorter microstate C duration in FTD compared with that in AD and controls [
11]. Another study observed an increased microstate B and microstate A duration in early-onset AD and FTD, respectively, along with reduced occurrences of microstates A–C in early-onset AD and reduced microstate C occurrence in FTD [
12]. Also, another study found that patients with semantic dementia lacked a typical microstate C but exhibited an atypical microstate E, which might indicate dysfunctional cognitive function integration [
13].
Despite these findings, methodological shortcomings limit their interpretation. For example, many prior studies did not apply grand mean fitting or achieved less than 80% explained variance [
12], while others lacked group mean maps or grand mean templates [
11,
13]. The lack of using global maps in these microstate analyses reduces their reliability and comparability because individual template maps introduce spatial variance across subjects and groups, which eventually increases the variance of microstates’ extracted characteristics [
14]. Moreover, most studies constrained analyses to four canonical microstates a priori, though recent work suggests that optimal clustering often exceeds four states, extending to 4–7 maps to better represent complicated networks of brain dynamics through more frequently alternating microstate maps with different topographies [
10,
15].
Together, these inconsistencies highlight the need for standardized analysis pipelines. To address this gap, in the present study, we apply a validated microstate workflow in MICROSTATELAB in EEGLAB [
16], focusing only on temporal parameters demonstrated to be reliable [
10]. Additionally, we introduce a ratio approach that normalizes each microstate parameter to the total across all microstates (e.g., relative duration of microstate A = duration of A ÷ total duration). This adjustment reduces inter-individual variability such as individual background activity (also known as 1/f noise) [
6] and may improve sensitivity for detecting group differences.
  3. Results
Across the participants, both the four- and seven-class clustering solutions were identified, and the resulting maps were consistent with those already published [
10] (
Figure 1). For the four-class solution, the shared variance with the published metamaps was 97.35%, 98.70%, 96.86%, and 86.54% for microstates A, B, C, and D, respectively (
Table 1).
The group comparisons revealed significant differences in the temporal parameters of several microstates. In the four-class solution, the ANCOVA and Kruskal–Wallis analyses indicated that the duration, coverage, relative duration, and relative occurrence of microstate B, as well as the occurrence and relative duration of microstate D, differed significantly across the CTL, FTD, and AD groups (
p < 0.05 for both parametric and nonparametric comparisons) (
Table 2).
The CTL group showed a significantly lower duration, coverage, relative duration, and relative occurrence in microstate B compared with both the AD and FTD groups (
p < 0.001, except for the duration of microstate B, where CTL vs. FTD showed 
p < 0.05). The occurrence of microstate D was significantly higher in the CTL group compared to the AD group (
p < 0.001) but not the FTD group, while the relative duration of microstate D was significantly higher in the CTL group compared to both the AD and FTD groups (
p < 0.001 and 
p < 0.01, respectively) (
Figure 2).
Linear regression analyses controlling age and gender confirmed that these temporal parameters were strongly related to the MMSE scores (
Table 3). Specifically, the duration, coverage, relative duration, and relative occurrence of microstate B, as well as the occurrence and relative duration of microstate D, were significant predictors of MMSE performance.
For the seven-class solution, the shared variance with published metamaps was 99.06%, 87.99%, 95.63%, 95.85%, 92.74%, 97.81%, and 92.17% for microstates A through G, respectively (
Table 4). The ANCOVA and Kruskal–Wallis analyses identified significant group differences in the duration, coverage, relative duration, and relative occurrence of microstate G and the occurrence, coverage, relative duration and relative occurrence of microstate C (
p < 0.05 for both parametric and nonparametric comparisons) (
Table 5).
In particular, the duration of microstate G was significantly longer in the AD group compared to that in the CTL group (
p < 0.001). Moreover, the coverage, occurrence, relative duration, and relative occurrence of microstate C were significantly higher in the CTL group compared to that in the AD and FTD groups, while the coverage, relative duration, and relative occurrence of microstate G were all significantly lower in the CTL group compared to the AD and FTD groups (
p < 0.001) (
Figure 3).
The regression analyses further demonstrated that the duration, coverage, relative duration, and relative occurrence of microstate G, together with the occurrence, coverage, relative duration, and relative occurrence of microstate C, were significantly associated with the MMSE scores (
Table 6).
  4. Discussion
The present study demonstrates that different clustering solutions in EEG microstate analysis reveal distinct but complementary markers of dementia. Using four-class clustering, the temporal parameters of microstates B and D differentiated healthy controls from both the AD and FTD groups. In contrast, with seven-class clustering, the temporal parameters of microstates C and G distinguished the controls from the dementia groups. In both clustering solutions, these microstate parameters were also significantly associated with cognitive status, as reflected in the MMSE scores, indicating that microstate parameters are associated with cognitive impairments in patients with dementia. Importantly, applying relative measures of duration and occurrence provided additional discriminatory power. For example, in the seven-class solution, the absolute duration of microstate C and the occurrence of microstate G did not significantly differ between groups, whereas their relative values successfully distinguished healthy controls from patients with dementia.
Overall, the results of the current study are not fully consistent with those reported in the previous literature. Unlike one previous study that discovered a shorter microstate C duration in patients with FTD [
11], there was no significance difference between the groups in terms of this parameter in our study. Also, in another study, increased microstate A duration and decreased microstate A occurrence were observed in the FTD and AD groups, respectively, but no difference in microstate A was discovered in the current study [
12]. However, some consistent findings include reduced occurrences of microstate C in early-onset AD and FTD [
12]. Such differences between studies might be derived from the use of different analysis procedures and parameters, which supports the importance of a standardized procedure, as was applied in the current study.
Although four- and seven-class solutions capture different numbers and topographies of microstates, both sets of maps showed a high shared variance with published template maps from meta-analyses [
14]. This correspondence supports the validity of our clustering results and aligns with the broader view that microstates reflect brief but functionally meaningful configurations of large-scale brain networks. Functional MRI studies have suggested that canonical microstates correspond to resting-state networks (RSNs), with microstate A linked to phonological processing, microstate B to the visual network, microstate C to the salience network, and microstate D to attentional networks [
22,
23]. Also, in the extended microstate maps, microstate E represents the interoceptive and emotion processing network, partially overlapping with the salience network in microstate C; microstate F reveals areas of the anterior default mode network that is responsible for the theory of mind and information processing; and microstate G is related to the somatosensory network [
24]. According to this framework, spontaneous brain activity alternates rapidly across RSNs, and microstates capture these transitions on the millisecond scale [
25]. From this perspective, the “duration” of the microstate reveals the stability of each RSN, the “occurrence” represents the frequency of activation of its RSNs, and the “coverage” indicates the relative time coverage of the related RSNs [
9]. However, mapping between microstates and RSNs remains controversial since EEG microstates operate on much shorter time scales than fMRI. Some studies report an association between microstates and the default mode network [
26], while others have not confirmed this relationship [
22]. Consequently, microstates that appear topographically similar across different clustering solutions, such as those labeled “B,” may nonetheless index distinct underlying RSNs. Therefore, the same label in the four- and seven-class clustering solutions in the current study might represent different functional correlates, which needs further investigation with comparisons to different neuroimaging techniques. This indicates that considering multiple clustering solutions may be important for fully characterizing the range of network dynamics in EEG microstate analysis.
Another novel strength of the present study is the use of ratio-normalized parameters, in which the duration or occurrence of each microstate is expressed relative to the total across all microstates. This approach reduces inter-individual variability, which is known to affect EEG microstate measures [
26], and may provide a more reliable index of temporal dynamics. Each temporal parameter captures a different aspect of large-scale network activity: duration reflects microstate stability, occurrence reflects the switching rate, and coverage reflects the relative dominance of a microstate. By normalizing duration and occurrence, we may more effectively capture relative changes in network stability and switching that accompany dementia. Although further work is needed to establish the precise neurophysiological meaning of relative parameters, our findings suggest that they provide useful complementary information for distinguishing clinical groups.
Our results further indicate that EEG microstates can serve as early and cost-effective screening markers for dementia. While they did not differentiate between AD and FTD, the microstate parameters we identified reliably distinguished both patient groups from healthy controls. The lack of a differential diagnosis between AD and FTD might be due to the overlapping patterns of neurodegeneration and behavioral symptoms [
3,
4]. As each subtype of AD and FTD represents different network dysfunctions and related biomarkers [
1,
2], further study is needed to investigate the effectiveness of EEG microstate parameters in classifying these dementia subtypes. For example, EEG microstate analysis of bvFTD might show abnormalities in microstate D due to its dysfunction in personality and behavior, while that of the semantic variant of FTD (primary progressive aphasia) might demonstrate a difference in microstate A, which is often related to language processing [
22,
23]. Nevertheless, our result aligns with recent recommendations highlighting the potential of EEG biomarkers for dementia diagnosis [
27]. A stratified diagnostic approach could therefore be envisioned, in which EEG microstate analysis is used as an inexpensive and noninvasive first-line screening tool to identify individuals at risk, followed by more costly or invasive methods such as MRI or PET for diagnostic confirmation. For example, patients with probable dementia could be initially screened with convenient EEG microstate analysis, and then more complex neuroimaging methods could be applied to identify the exact type of dementia. Such a tiered approach would lower costs, improve accessibility, and facilitate earlier detection of this condition.
There are some limitations to our study, however. The small sample size and the retrospective design employed complicate the practical evaluation of microstate parameters as diagnostic biomarkers. Further investigations with larger sample sizes, prospective designs, and multi-center cohorts with more detailed clinical information such as subtypes of dementia are needed to fully evaluate whether microstate parameters are effective in classifying neurological abnormalities. Also, there is no patient information on biomarkers such as amyloid and tau in cerebrospinal fluid or PET included in the current study. This limits further comparison with other biomarkers and provides a pathophysiological perspective on patients with dementia related to EEG microstate parameters. Additionally, provided that MMSE scores are associated with our significant parameters, further investigation is needed to elucidate the relationship between our significant parameters and other clinical scores to discover their cognitive correlates.
Nevertheless, the current study is valuable as an exploratory analysis of EEG microstates as promising dementia biomarkers. EEG has been investigated for decades as a useful source of biomarkers of neurological disorders. For example, the spectral theta/beta ratio has been approved by the Food and Drug Administration (FDA) for the assessment of attention-deficit hyperactivity disorder (ADHD) as a supporting biomarker that improves the diagnostic accuracy when combined with clinical information, but not when used alone [
28]. Also, EEG mismatch negativity (MMN) is a promising tool for monitoring biomarkers to track physiological alterations following interventions and disease progression [
29]. Future studies concentrating on the clinical values of microstate dynamics as supporting—but not diagnostic—biomarkers might also be important for the clinical validation of EEG biomarkers.
Overall, the present findings suggest that temporal parameters of microstates B and D in the four-class solution and microstates C and G in the seven-class solution are promising candidates as biomarkers for distinguishing patients with dementia from healthy individuals. While they may not differentiate AD from FTD, they provide a valuable step toward scalable and early screening methods. Future work should aim to expand on these findings by using larger cohorts, prospective designs, and classification analyses to further establish the diagnostic utility and accuracy of microstate-based biomarkers.