Classification of Mild Cognitive Impairment, Alzheimer’s Disease, and Healthy ControlsBased on Weighted Random Forest-KNN
Yuan Yuyang1, Li Fangyun2, Li Yingjie1#*, Li Yunxia2#*
1(School of Life Sciences, Shanghai University, Shanghai 200444, China) 2(Department ofNeurology,Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China)
Abstract:Mild cognitive impairment (MCI), a critical prodromal stage of Alzheimer's disease (AD), exhibits distinct neural oscillatory features from healthy controls (HC). These differences are pivotal for early AD diagnosis and research on cognitive aging mechanisms. Brain functional connectivity in the α-band (8~13 Hz) has been proven to be closely associated with resting-state network activity, yet its classification efficacy and key biomarkers across MCI, AD, and HC populations remain incompletely elucidated. Meanwhile, traditional machine learning algorithms inadequately assign weights to high-dimensional EEG features, making it difficult to capture subtle differences among multiple groups. This study employed a feature importance weighting strategy via random forest to enhance the discriminability of critical brain connections in traditional machine learning models, addressing the inefficient feature utilization of single models. Resting-state EEG data from 43 participants each in MCI, AD, and HC groups were analyzed. A full feature matrix (AFM) for the α-band was constructed using Pearson correlation coefficients (PCC), and brain connections with significant inter-group differences were filtered via analysis of variance (ANOVA) to form an effective feature matrix (EFM). An integrated weighted random forest-KNN (WRF-KNN) model was designed, and its performance in three-class (MCI/AD/HC) and two-class (MCI/AD) tasks was evaluated using 5-fold stratified cross-validation. Additionally, a network of critical brain connections was constructed based on the feature importance of random forest. The WRF-KNN model achieved an average accuracy of 93% ±2.1% in the three-class task, significantly outperforming single KNN (88% ± 3.5%) and random forest (90% ± 2.8%, P < 0.05); its accuracy in MCI-AD two-class classification reached 92%±1.8%. Concurrently, the model identified 20 critical α-band connections. Their importance scores revealed key differences in α-band neural oscillations and functional connectivity between MCI/AD patients and HC, MCI and AD groups exhibited reduced prefrontal-parietal connectivity and enhanced intra-occipital connectivity, whereas HC displayed a more uniform connection distribution. These findings open new perspectives for the early diagnosis of AD and research on cognitive aging.
袁宇阳, 李芳云, 李颖洁, 李云霞. 基于加权随机森林-K近邻的轻度认知障碍、阿尔茨海默病和健康对照分类研究[J]. 中国生物医学工程学报, 2026, 45(4): 482-494.
Yuan Yuyang, Li Fangyun, Li Yingjie, Li Yunxia. Classification of Mild Cognitive Impairment, Alzheimer’s Disease, and Healthy ControlsBased on Weighted Random Forest-KNN. Chinese Journal of Biomedical Engineering, 2026, 45(4): 482-494.
[1] Scheltens P,De Strooper B,Kivipelto M,et al. Alzheimer's disease[J]. The Lancet,2021,397(10284):1577-1590. [2] Petersen RC. Mild cognitive impairment as a diagnostic entity[J]. Journal of Internal Medicine,2004,256(3):183-194. [3] Park DC,Reuter-Lorenz PA. The adaptive brain: aging and neurocognitive scaffolding[J]. Annual Review of Psychology,2009,60:173-196. [4] Frisoni GB,Boccardi M,Barkhof F,et al. Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers[J]. The Lancet Neurology,2017,16(8):661-676. [5] Cassani R,Estarellas M,San-Martin R,et al. Systematic review on resting-state EEG for Alzheimer's disease diagnosis and progression assessment[J]. Disease Markers,2018,2018:5174815. [6] Buzsaki G,Draguhn A. Neuronal oscillations in cortical networks[J]. Science,2004,304(5679):1926-1929. [7] Paitel ER,Otteman CBD,Polking MC,et al. Functional and effective EEG connectivity patterns in Alzheimer's disease and mild cognitive impairment: a systematic review[J]. Frontiers in Aging Neuroscience,2025,17:1496235. [8] Binnewijzend MAA,Schoonheim MM,Sanz-Arigita E,et al. Resting-state fMRI changes in Alzheimer's disease and mild cognitive impairment[J]. Neurobiology of Aging,2012,33(9):2018-2028. [9] Lopez ME,Bruna R,Aurtenetxe S,et al. Alpha-band hypersynchronization in progressive mild cognitive impairment: a magnetoencephalography study[J]. Journal of Neuroscience,2014,34(44):14551-14559. [10] Stam CJ,de Haan W,Daffertshofer A,et al. Graph theoretical analysis of magnetoencephalographic functional connectivity in Alzheimer's disease[J]. Brain,2009,132(1):213-224. [11] Rathore S,Habes M,Iftikhar MA,et al. A review on neuroimaging-based classification studies and associated feature extraction methods for Alzheimer's disease and its prodromal stages[J]. NeuroImage,2017,155:530-548. [12] Fiscon G,Weitschek E,Cialini A,et al. Combining EEG signal processing with supervised methods for Alzheimer's patients classification[J]. BMC Medical Informatics and Decision Making,2018,18(1):35. [13] Ieracitano C,Mammone N,Bramanti A,et al. A convolutional neural network approach for classification of dementia stages based on 2D-spectral representation of EEG recordings[J]. Neurocomputing,2019,323:96-107. [14] Zheng X,Wang B,Liu H,et al. Diagnosis of Alzheimer's disease via resting-state EEG: integration of spectrum, complexity, and synchronization signal features[J]. Frontiers in Aging Neuroscience,2023,15:1288295. [15] Wang J,Zuo X,Dai Z,et al. Disrupted functional brain connectome in individuals at risk for Alzheimer's disease[J]. Biological Psychiatry,2013,73(5):472-481. [16] Wang X,Cui X,Ding CL,et al. Deficit of cross-frequency integration in mild cognitive impairment and Alzheimer's disease: a multilayer network approach[J]. Journal of Magnetic Resonance Imaging,2021,53(5):1387-1398. [17] Folstein MF,Folstein SE,McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician[J]. Journal of Psychiatric Research,1975,12(3):189-198. [18] Nasreddine ZS,Phillips NA,Bedirian V,et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment[J]. Journal of the American Geriatrics Society,2005,53(4):695-699. [19] Lawton MP,Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living[J]. The Gerontologist,1969,9(3 Pt 1):179-186. [20] Morris JC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type[J]. International Psychogeriatrics,1997,9(S1):173-176. [21] Hamilton M. The assessment of anxiety states by rating[J]. British Journal of Medical Psychology,1959,32(1):50-55. [22] Hamilton M. A rating scale for depression[J]. Journal of Neurology, Neurosurgery, and Psychiatry,1960,23(1):56-62. [23] Petersen RC,Smith GE,Waring SC,et al. Mild cognitive impairment: clinical characterization and outcome[J]. Archives of Neurology,1999,56(3):303-308. [24] McKhann GM,Knopman DS,Chertkow H,et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J]. Alzheimer's & Dementia,2011,7(3):263-269. [25] 中国痴呆与认知障碍诊治指南写作组,中国医师协会神经内科医师分会认知障碍疾病专业委员会. 2018中国痴呆与认知障碍诊治指南(五):轻度认知障碍的诊断与治疗[J]. 中华医学杂志,2018,98(17):1294-1301. [26] World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects[J]. JAMA,2013,310(20):2191-2194. [27] Allen EA,Damaraju E,Plis SM,et al. Tracking whole-brain connectivity dynamics in the resting state[J]. Cerebral Cortex,2014,24(3):663-676. [28] Sakkalis V. Review of advanced techniques for the estimation of brain connectivity measured with EEG/MEG[J]. Computers in Biology and Medicine,2011,41(12):1110-1117. [29] Hutchison RM,Womelsdorf T,Allen EA,et al. Dynamic functional connectivity: promise, issues, and interpretations[J]. NeuroImage,2013,80:360-378. [30] Srinivasan R,Winter WR,Ding J,et al. EEG and MEG coherence: measures of functional connectivity at distinct spatial scales of neocortical dynamics[J]. Journal of Neuroscience Methods,2007,166(1):41-52. [31] Kolmogorov AN. Sulla determinazione empirica di una legge di distribuzione[J]. Giornale dell'Istituto Italiano degli Attuari,1933,4:83-91. [32] Kruskal WH,Wallis WA. Use of ranks in one-criterion variance analysis[J]. Journal of the American Statistical Association,1952,47(260):583-621. [33] Dunn OJ. Multiple comparisons among means[J]. Journal of the American Statistical Association,1961,56(293):52-64. [34] Cover TM,Hart PE. Nearest neighbor pattern classification[J]. IEEE Transactions on Information Theory,1967,13(1):21-27. [35] Breiman L. Random forests[J]. Machine Learning,2001,45(1):5-32. [36] Powers DMW. Evaluation: from precision, recall and F-measure to ROC, informedness, markedness and correlation[J]. Journal of Machine Learning Technologies,2011,2(1):37-63. [37] Jensen O,Mazaheri A. Shaping functional architecture by oscillatory alpha activity: gating by inhibition[J]. Frontiers in Human Neuroscience,2010,4:186. [38] Pijnenburg YA,van der Made Y,van Cappellen van Walsum AM,et al. EEG synchronization likelihood in mild cognitive impairment and Alzheimer's disease during a working memory task[J]. Clinical Neurophysiology,2004,115(6):1332-1339. [39] Babiloni C,Arakaki X,Azami H,et al. Measures of resting state EEG rhythms for clinical trials in Alzheimer's disease: recommendations of an expert panel[J]. Alzheimer's & Dementia,2021,17(9):1528-1553. [40] Clayton MS,Yeung N,Cohen Kadosh R. The many characters of visual alpha oscillations[J]. European Journal of Neuroscience,2018,48(7):2498-2508. [41] Vogel JW,Young AL,Oxtoby NP,et al. Four distinct trajectories of tau deposition identified in Alzheimer's disease[J]. Nature Medicine,2021,27(5):871-881. [42] Lizio R,Babiloni C,Del Percio C,et al. Different abnormalities of cortical neural synchronization mechanisms in patients with mild cognitive impairment due to Alzheimer's and chronic kidney diseases: an EEG study[J]. Journal of Alzheimer's Disease,2018,65(3):897-915. [43] Michels L,Muthuraman M,Anwar AR,et al. Changes of functional and directed resting-state connectivity are associated with neuronal oscillations, ApoE genotype and amyloid deposition in mild cognitive impairment[J]. Frontiers in Aging Neuroscience,2017,9:304. [44] Poil SS,de Haan W,van der Flier WM,et al. Integrative EEG biomarkers predict progression to Alzheimer's disease at the MCI stage[J]. Frontiers in Aging Neuroscience,2013,5:58. [45] Azami H,Zrenner C,Brooks H,et al. Beta to theta power ratio in EEG periodic components as a potential biomarker in mild cognitive impairment and Alzheimer's dementia[J]. Alzheimer's Research & Therapy,2023,15(1):133. [46] Klimesch W. EEG alpha and theta oscillations reflect cognitive and memory performance: a review and analysis[J]. Brain Research Reviews,1999,29(2-3):169-195. [47] Huang L,Hu W,Cui L,et al. Temporo-frontoparietal hypoconnectivity as a biomarker for isolated language impairment in mild cognitive impairment: a cross-cohort comparison[J]. Alzheimer's & Dementia,2024,20(9):6566-6578.