Profiling characteristics of plasma exosomal miRNAs across cognitive stages: from normalcy to mild cognitive impairment and Alzheimer's disease.

The rising global prevalence of Alzheimer's disease (AD) and mild cognitive impairment (MCI) underscores the urgent need to elucidate their underlying pathogenic mechanisms. This study investigated the dynamic alterations of plasma-derived exosomal miRNAs across the cognitive spectrum from normal cognition (NC) through MCI to AD, and their potential pathogenetic implications. Here, we enrolled 10 AD patients, 9 MCI patients, and 10 normal cognitive (NC) patients rigorously diagnosed using amyloid PET imaging, cerebrospinal fluid biomarkers, and standardized neuropsychological assessments. Serum exosomes were isolated and identified, then small RNA sequencing was performed. The results revealed distinct exosomal miRNA expression profiles across disease stages, with 10 conserved miRNAs showing progressive dysregulation along the NC-MCI-AD continuum. Target gene prediction formed numerous miRNA-mRNA pairs. GO and KEGG enrichment indicated that exosomal miRNAs might affect cognitive decline by regulating neurodevelopment and cell senescence. Strikingly, ROC analysis demonstrated superior diagnostic performance for miR-151a-3p and miR-210-3p in distinguishing disease states. Our findings not only characterize stage-specific exosomal miRNA signatures during AD progression but also identify novel circulating biomarkers with diagnostic potential. This work provides mechanistic insights into exosome-mediated pathological processes and advances the development of liquid biopsy approaches for early detection and therapeutic monitoring in neurodegenerative diseases.