Abstract
BACKGROUND: Recently, microRNAs (miRNAs) have attracted significant interest as predictive biomarkers for various types of dementia, including Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), normal pressure hydrocephalus (NPH), and mild cognitive impairment (MCI). Machine learning (ML) methods enable the integration of miRNAs into highly accurate predictive models of dementia. OBJECTIVE: To investigate the differential expression of miRNAs across dementia subtypes compared to normal controls (NC) and analyze their enriched biological and disease pathways. Additionally, to evaluate the use of these miRNAs in binary and multiclass ML models for dementia prediction in both overall and sex-specific datasets. METHODS: Using data comprising 1685 Japanese individuals (GSE120584 and GSE167559), we performed differential expression analysis to identify miRNAs associated with five dementia groups in both overall and sex-specific datasets. Pathway enrichment analyses were conducted to further analyze these miRNAs. ML classifiers were used to create predictive models of dementia. RESULTS: We identified novel differentially expressed miRNA biomarkers distinguishing NC from five dementia subtypes. Incorporating these miRNAs into ML classifiers resulted in up to a 27% improvement in dementia risk prediction. Pathway analysis highlighted neuronal and eye disease pathways associated with dementia risk. Sex-specific analyses revealed unique biomarkers for males and females, with miR-128-1-5 as a protective factor for males in AD, VaD, and DLB, and miR-4488 as a risk factor for female AD, highlighting distinct pathways and potential therapeutic targets for each sex. CONCLUSIONS: Our findings support existing dementia etiology research and introduce new potential and sex-specific miRNA biomarkers.