Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles of hyperphosphorylated tau, synaptic dysfunction, and chronic neuroinflammation. AD pathogenesis involves multiple central nervous system (CNS) cell types-including neurons, astrocytes, microglia, and oligodendrocytes, and, less prominently, neural stem cells (NSCs), ependymal cells, and endothelial cells-which undergo coordinated but cell-type-specific pathological changes. These include neuronal loss, reactive gliosis, impaired myelin maintenance, reduced neurogenesis, and blood-brain barrier (BBB) dysfunction. MicroRNAs (miRNAs), the small non-coding RNAs that regulate post-transcriptional gene expression, have emerged as key modulators of these cell-specific processes and are consistently dysregulated in AD. Across AD-vulnerable brain regions and CNS cell types, miRNAs influence amyloid and tau biology, synaptic resilience, glial activation states, myelin structure, neurogenic potential, and vascular homeostasis. Dysregulated miRNAs also act across cell types through extracellular vesicle (EV) transfer, amplifying or mitigating amyloidogenesis, tauopathy, neuroinflammation, and white-matter injury. This review provides a comprehensive, cell-type-specific analysis of miRNAs involved in AD, detailing their roles in neurons, astrocytes, microglia, oligodendrocytes, NSCs, ependymal cells, and endothelial cells. We highlight common miRNAs that function across multiple CNS cell types and examine the potential of circulating and cerebrospinal fluid (CSF) miRNAs as minimally invasive biomarkers. Finally, we discuss therapeutic strategies aimed at restoring protective miRNAs or inhibiting pathogenic miRNAs, emphasizing the need for targeted interventions. By integrating pathways of miRNA dysregulation across CNS cell types, this review underscores the central role of miRNA networks in AD pathogenesis and the promise of precise, cell-specific miRNA modulation.