Plasma Extracellular Vesicle MicroRNA Analysis of Alzheimer’s Disease Reveals Dysfunction of a Neural Correlation Network

Small extracellular vesicle (sEV) is an emerging source of potential biomarkers of Alzheimer's disease (AD), but the role of microRNAs (miRNAs) in sEV is not well understood. In this study, we conducted a comprehensive analysis of sEV-derived miRNAs in AD using small RNA sequencing and coexpression network analysis. We examined a total of 158 samples, including 48 from AD patients, 48 from patients with mild cognitive impairment (MCI), and 62 from healthy controls. We identified an miRNA network module (M1) that was strongly linked to neural function and showed the strongest association with AD diagnosis and cognitive impairment. The expression of miRNAs in the module was decreased in both AD and MCI patients compared to controls. Conservation analysis revealed that M1 was highly preserved in the healthy control group but dysfunctional in the AD and MCI groups, suggesting that changes in the expression of miRNAs in this module may be an early response to cognitive decline prior to the appearance of AD pathology. We further validated the expression levels of the hub miRNAs in M1 in an independent population. The functional enrichment analysis showed that 4 hub miRNAs might interact with a GDF11-centered network and play a critical role in the neuropathology of AD. In summary, our study provides new insights into the role of sEV-derived miRNAs in AD and suggests that M1 miRNAs may serve as potential biomarkers for the early diagnosis and monitoring of AD.