MicroRNA biomarkers in cerebrospinal fluid and plasma predicting cognitive decline in Alzheimer's disease

Background MicroRNAs (miRNAs) have emerged as key regulators in Alzheimer's disease (AD), yet their function as biomarkers remains uncertain due to inconsistent findings in blood and cerebrospinal fluid (CSF). Objective We aimed to identify miRNAs that track disease progression, providing valuable insights into AD pathophysiology. Methods This study focused on analyzing alterations in miRNA expression levels in CSF and plasma samples, and their association with cognitive decline and hippocampal volume changes in AD patients using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Results Integrative analyses identified a consistent set of miRNA alterations associated with AD. While a t-test showed a selective decrease of CSF miR-185-5p in AD versus healthy controls, logistic regression identified broader signatures in plasma (hsa-miR-125b-5p, hsa-miR-26a-5p, hsa-miR-376a-3p) and CSF (hsa-miR-499a-3p, alongside CSF hsa-miR-146a-5p, hsa-miR-16-5p, and hsa-miR-185-5p). LASSO regression further refined these to a reproducible decrease in plasma hsa-miR-125b-5p and CSF hsa-miR-185-5p, alongside an increase in plasma hsa-miR-26a-5p in AD. Together, these approaches reveal convergent miRNA dysregulation in plasma and CSF, suggesting their relevance to AD pathophysiology. Further analysis showed that lower plasma hsa-miR-125b-5p and hsa-miR-26a-5p, as well as lower CSF hsa-miR-185-5p, were associated with accelerated cognitive decline measured by ADAS13 scores. Reduced CSF hsa-miR-185-5p was significantly linked to hippocampal atrophy, with similar trends for the plasma miRNAs. Furthermore, CSF hsa-miR-185-5p levels correlated with amyloid pathology, suggesting a potential role in AD pathology. Conclusions These results highlight the role of CSF and plasma miRNA biomarkers in predicting cognitive and clinical decline in patients with AD.