Cognitive MMN and P300 in mild cognitive impairment and Alzheimer’s disease: a high density EEG-3D vector field tomography approach
Abstract
Precise preclinical detection of dementia for effective treatment and stage monitoring is of great importance. Miscellaneous types of biomarkers, e.g., biochemical, genetic, neuroimaging, and physiological, have been proposed to diagnose Alzheimer's disease (AD), the usual suspect behind manifested cognitive decline, and mild cognitive impairment (MCI), a neuropathology prior to AD that does not affect cognitive functions. Event related potential (ERP) methods constitute a non-invasive, inexpensive means of analysis and have been proposed as sensitive biomarkers of cognitive impairment; besides, various ERP components are strongly linked with working memory, attention, sensory processing and motor responses. In this study, an auditory oddball task is employed, to acquire high density electroencephalograhy recordings from healthy elderly controls, MCI and AD patients. The mismatch negativity (MMN) and P300 ERP components are then extracted and their relationship with neurodegeneration is examined. Then, the neural activation at these components is reconstructed using the 3D vector field tomography (3D-VFT) inverse solution. The results reveal a decline of both ERPs amplitude, and a statistically significant prolongation of their latency as cognitive impairment advances. For the MMN, higher brain activation is usually localized in the inferior frontal and superior temporal gyri in the controls. However, in AD, parietal sites exhibit strong activity. Stronger P300 generators are mostly found in the frontal lobe for the controls, but in AD they often shift to the temporal lobe. Reduction in inferior frontal source strength and the switch of the maximum intensity area to parietal and superior temporal sites suggest that these areas, especially the former, are of particular significance when neurodegenerative disorders are investigated. The modulation of MMN and P300 can serve to produce biomarkers of dementia and its progression, and brain imaging can further contribute to the diagnostic efficiency of ERPs.
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Previous literature supports that individuals with Alzheimer's disease have impaired predictive processes.
“previous literature supporting the fact that individuals with Alzheimer ' s disease have impaired pre dictive processes (Papadaniil et al., 2016; Tsolaki et al., 2017).”
From Predictive coding in neuropsychiatric disorders: a systematic transdiagnostic review. (2025) · cites this paper as Papadaniil et al., 2016
Parietal mismatch responses are particularly sensitive to AD.
“with parietal mismatch responses being particularly sensitive to AD. 31 , 34”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [34]
Previous mismatch negativity studies have shown differences between people with AD and controls.
“Previous mismatch negativity studies have shown differences between people with AD and controls. 34 , 35”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [34]
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“…Jahanshahi, & Kopp, 2016; Solı́s-Vivanco et al., 2011), Alzheimer’s disease (Idrizbegovic, Hederstierna, & Rosenhall, 2016; Jiang et al., 2017; Papadaniil et al., 2016; Pekkonen, 2000; Pekkonen, Hirvonen, Jääskeläinen, Kaakkola, & Huttunen, 2001; Tsolaki et al., 2017), autism…”
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Auditory event-related potentials in individuals with subjective and mild cognitive impairment
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Playing a P300-based BCI VR game leads to changes in cognitive functions of healthy adultsPreprint
Bulat, M., Karpman, A., Samokhina, A., & Panov, A. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.28.118281 · Cited by 9 · see citing works
Combining Nonlinear Features of EEG and MRI to Diagnose Alzheimer’s Disease
Rad, E. M., Azarnoosh, M., Ghoshuni, M., & Khalilzadeh, M. (2024) · Annals of Data Science · doi:10.1007/s40745-024-00533-4 · Cited by 8 · see citing works
“In this study, a 2-layer Elman neural network was used, which had eight neurons in the latent layer and one neuron in the output layer [27].”
Applications of event-related potentials in Alzheimer’s disease: a systematic review and analysis
Liang, Q., Chen, Z., Tang, X., & Wang, X. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1513049 · Cited by 8 · see citing works
“…(Horvath et al., 2018), reflecting the degree of cognitive impairment in AD higher than in healthy older adults (Chrysa and Papadaniil, 2016; Chrysa and Papadaniil, 2016), indicating that AD patients have impaired attention and reduced auto-processing ability and MMN may be able to predict…”
InfluentialYue, T., Chen, Y., Zheng, Q., Xu, Z., Wang, W., & Ni, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.677090 · Cited by 8 · see citing works
“Studies have shown that with the development of neurodegenerative diseases, the amplitude of P300 decreases while the latency increases (Papadaniil et al., 2016; Tsolaki et al., 2017).”
BackgroundSingle channel EEG time-frequency features to detect Mild Cognitive Impairment
Khatun, S., Morshed, B. I., & Bidelman, G. M. (2017) · IEEE International Symposium on Medical Measurements and Applications (MeMeA) · doi:10.1109/memea.2017.7985916 · Cited by 8 · see citing works
“The acceptable limit for RTs considered here was 200 - 1500 ms [8-9].”
BackgroundMethodInfluentialAdjunct Methods for Alzheimer’s Disease Detection: A Review of Auditory Evoked Potentials
Wei, G., Tian, X., Hong, Y., Luo, Y., Liu, G., Sun, S., Wang, X., & Wen, H. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230822 · Cited by 8 · see citing works
Toural, J. E. S., Pedrón, A. M., & Reyes, E. J. M. (2021) · Informatics in Medicine Unlocked · doi:10.1016/j.imu.2021.100537 · Cited by 6 · see citing works
Lanskey, J. H., Jafarian, A., Hughes, L. E., Karadag, M., Kocagöncü, E., Rouse, M. A., Adams, N., Naessens, M., Raymont, V., Woolrich, M. W., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03288-3 · Cited by 5 · see citing works
Wang, C., Yu, W., Xu, T., Zeng, H., Cuello, A. M. G., Fernández‐Villalba, E., Xu, F., Chu, F., Herrero, M. T., & Tao, M. (2024) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2024.72 · Cited by 5 · see citing works
“Similar to previous literature (e.g., 18, 29), our current study reported the elongated P3 latencies in AD compared to both Controls and MCI under all three external emotions.”
InfluentialAuditory Event-Related Potentials in Older Adults with Subjective Memory Complaints
Tarawneh, H. Y., Jayakody, D. M. P., Verma, S., Doré, V., Xia, Y., Mulders, W. H. A. M., Martins, R. N., & Sohrabi, H. R. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221119 · Cited by 5 · see citing works
Recent Advances in Clinical Applications of P300 and MMN
Falkenstein, M. (2023) · Neuromethods · doi:10.1007/978-1-0716-3545-2_1 · Cited by 5 · see citing works
Poskotinova, L. V., Минувалиевна, Х. Н., Kharak, A., Krivonogova, O., & Вячеславовна, К. Е. (2023) · Diagnostics · doi:10.3390/diagnostics13091598 · Cited by 4 · see citing works
“The decrease in the strength of the lower frontal source in P300 generation and the shifting of the zone of maximum intensity to the parietal and upper temporal regions of the brain suggest that these areas are of particular importance in the study of neurodegenerative diseases [22].”
BackgroundBell, K. L., Lister, J. J., Conter, R., Bush, A. L. H., & O’Brien, J. L. (2020) · Experimental Aging Research · doi:10.1080/0361073x.2020.1861838 · Cited by 4 · see citing works
The mismatch negativity as an index of cognitive abilities in adults with Down syndrome
Saini, F., Masina, F., Wells, J., Rosch, R. E., Hamburg, S., Startin, C. M., & Strydom, A. (2023) · Cerebral Cortex · doi:10.1093/cercor/bhad233 · Cited by 4 · see citing works
Exploring Aesthetic Perception in Impaired Aging: A Multimodal Brain—Computer Interface Study
Clemente, L., Rocca, M. L., Paparella, G., Delussi, M. D., Tancredi, G., Ricci, K., Procida, G., Introna, A., Brunetti, A., Taurisano, P., et al. (2024) · Sensors · doi:10.3390/s24072329 · Cited by 3 · see citing works
“Finally, this study highlights the potential of BCIs in the clinical setting, but further research is needed to refine interfaces and analysis techniques for targeted clinical applications.”
BackgroundThe effect of Alzheimer’s disease and its progression on pyramidal cell gain and connectivityPreprint
Lanskey, J. H., Jafarian, A., Karadag, M., Kocagöncü, E., Williams, R., Yadav, P., Quinn, A. J., Pitt, J., Thayanandan, T., Lowe, S. L., et al. (2024) · medRxiv · doi:10.1101/2024.04.11.24305662 · Cited by 3 · see citing works
Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity
Lanskey, J. H., Jafarian, A., Karadag, M., Kocagoncu, E., Williams, R. S., Yadav, P., Quinn, A. J., Pitt, J., Thayanandan, T., Lowe, S., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70805 · Cited by 2 · see citing works
“31,34 We defined multiple, alternative, symmetric model architectures, each representing plausible alternative hierarchical relationships between regions and their connectivity to include the inferior parietal cortex.”
Meta-Analyses of Auditory Evoked Potentials as Alzheimer Biomarkers
Bayat, A., Mirmomeni, G., Aiken, S. J., & Jafari, Z. (2025) · Ear and Hearing · doi:10.1097/aud.0000000000001718 · Cited by 2 · see citing works
Kamal, F., Morrison, C., Campbell, K. B., & Taler, V. (2021) · Neuroimage Reports · doi:10.1016/j.ynirp.2021.100074 · Cited by 2 · see citing works
“Ji et al. (2015) and Papadaniil et al. (2016) also failed to observe MMN differences between healthy older adults and people with MCI when using frequency deviants.”
Functional Connectivity Analysis of Visually Evoked ERPs for Mild Cognitive Impairment: Pilot Study
Antar, M., Wang, L., Tran, A., White, A. T., Williams, P. M., Sylcott, B., Mizelle, J. C., & Kim, S. Y. (2023) · Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) · doi:10.1109/embc40787.2023.10339999 · Cited by 2 · see citing works
“This study proposes utilizing visually evoked event-related potentials (ERP), particularly the P300 component that is directly linked to cognitive processes such as memory and attention [8].”
BackgroundMethodInfluentialLaub, C. E. (2010) · Lincoln (University of Nebraska) · Cited by 2 · see citing works
VR-based approach for MCI assessment system using fNIRS and graph convolutional network
Zhang, Y., Li, F., Bu, L., Su, H., & Bu, Y. (2025) · Biomedical Signal Processing and Control · doi:10.1016/j.bspc.2025.108472 · Cited by 1 · see citing works
Shi, X. N., Zhao, R. N., Yang, X., Wang, Z. N., Geng, C. N., & Tian, J. N. (2025) · Revista de Neurología · doi:10.31083/rn45402 · Cited by 1 · see citing works
“…(MoCA) P300 provides rater-independent, quantitative indices (latency and amplitude) that can capture subtle electrophysiological alterations potentially preceding overt behavioral changes, thereby complementing scale-based assessments and facilitating objective longitudinal monitoring [18,19].”
Bae, J.-H., Choi, M., Lee, K. H., & Kim, J. U. (2026) · Alzheimer s Research & Therapy · doi:10.1186/s13195-025-01940-2 · Cited by 1 · see citing works
“Notably, most previous studies have been conducted in laboratory settings with relatively small sample sizes, limiting the translational potential of their findings in clinical contexts [26, 27].”
Ušacka, A., Šneidere, K., Freibergs, Z., & Stepens, A. (2026) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2026.113423 · Cited by 1 · see citing works
Vision Sensors - Recent Advances
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EEG reveals key features of binocular color fusion and rivalry
Lv, Z., Yu, S., Jin, X., Liu, X., Dai, M., Yun, L., & Chen, Z. (2025) · Brain and Cognition · doi:10.1016/j.bandc.2025.106268 · Cited by 1 · see citing works
Pathological forgetting from a predictive processing perspective
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EEG and MRI Processing for Alzheimer’s Diseases
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Development and applications of a smartphone-based mobile electroencephalography (EEG) system
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Thee, K. W., Nisar, H., Yeap, K. H., & Tan, W. M. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/639815
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Experimental Medicine Approaches in Early-Phase CNS Drug Development
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Krivonogova, O., Вячеславовна, К. Е., & Poskotinova, L. V. (2024) · Экология человека · doi:10.17816/humeco633767
Evaluating P300 Latency as a Physiological Marker for Asymptomatic and Prodromal Alzheimer’s DiseasePreprint
Mohamed, M., Mohamed, N., Lee, J. J., Choi, K. Y., Kim, B. C., Gwak, J., Lee, K. H., & Kim, J. G. (2025) · Research Square · doi:10.21203/rs.3.rs-6525416/v1
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“Similarly, Papadaniil et al. (2016) did not find differences in the MMN between healthy older adults and those with mild cognitive impairment; however, they did find differences between these two groups and those with AD, who exhibited a lower amplitude of the MMN component.”
Enhanced Contour‐Deviant Mismatch Negativity and Mnemonic Representations in Older Musicians
Bugos, J. A., Chow, R., Mo, S., Rosenbaum, R. S., & Alain, C. (2026) · European Journal of Neuroscience · doi:10.1111/ejn.70576
Dopamine Compensates for Amyloid-Induced Default Mode Network Dysfunction to Support LearningPreprint
Giorgio, J., Morin, T., Chen, H.-Y., Berry, A. S., Breakspear, M. J., & Jagust, W. J. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.07.07.736872
- Authors
- Papadaniil, C. D., Kosmidou, V. E., Tsolaki, A., Tsolaki, M., Kompatsiaris, I. (., & Hadjileontiadis, L. J.
- Affiliations
- Aristotle University of Thessaloniki (GR)
- Information Technologies Institute (GR)
- Corresponding author
- Papadaniil, Chrysa D.
- Hadjileontiadis, Leontios J.
- ORCID
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 1648
- Issue
- Pt A
- Pages
- 425-433
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2496393055
- Cited by
- 71
- References
- 60
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 12 · 2023: 7 · 2022: 8 · 2021: 12 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 2
- FWCI
- 2.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- ARISTEIA (440)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › EEG and Brain-Computer Interfaces
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- mismatch negativity, P300, mild cognitive impairment, Alzheimer's disease, auditory oddball paradigm, event-related potentials, EEG source localization, dementia biomarkers, inferior frontal gyrus, superior temporal gyrus, parietal activation, neurodegeneration
- MeSH terms
- Acoustic Stimulation, Aged, Alzheimer Disease, Auditory Perception, Cerebral Cortex, Electroencephalography, Evoked Potentials, Auditory, Female, Frontal Lobe, Humans, Male, Middle Aged, Parietal Lobe, Temporal Lobe, Biomarkers, Disease Progression, Event-Related Potentials, P300, Cognitive Dysfunction
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