OBJECTIVE: Blood DNA methylation (DNAm) alterations have been widely reported in the onset and progression of mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, DNAm is underutilized as a diagnostic biomarker for these diseases. We aimed to evaluate the diagnostic performance of DNAm for MCI and AD, both individually and in combination with well-established AD biosignatures.
METHODS: A total of 1,891 blood samples from Alzheimer's Disease Neuroimaging Initiative (ADNI) studies were used to identify potential candidate DNAm biomarkers. Multimodal clinical data from 635 samples (normal control (NC), = 193; MCI, = 352; AD, = 90) in the TADPOLE dataset were utilized to construct eight different classification models using a graph convolutional network, a machine learning framework. n n n
RESULTS: After feature selection, 17 DNAm sites were selected for subsequent analysis. Remarkable differences in DNAm levels were observed at the screened DNAm loci in all three cohorts. Adopting DNAm features into multimodal models significantly improved the classification performance for three dichotomous subtasks (NC vs. non-NC, MCI vs. non-MCI, and AD vs. non-AD), especially when combined with cerebrospinal fluid (CSF) features for NC (area under the curve (AUC): 0.8534) and MCI classification (AUC: 0.7675). A weak correlation between DNAm and both magnetic resonance imaging and CSF features in the NC and MCI cohorts suggests good complementarity between modalities (correlation coefficient ≤0.2).
CONCLUSIONS: Our study offers new insights into peripheral DNAm in MCI and AD and suggests promising diagnostic performance of models integrating epigenomics, imaging, or CSF biomarkers.
PLAIN LANGUAGE SUMMARY TITLE: Using Machine Learning and Blood-Based Genetic Markers to Help Diagnose Mild Cognitive Impairment and Alzheimer's Disease.
