Noncoding RNA control of neuroinflammation in Alzheimer’s disease: from immune cell states to precision therapeutics

Neuroinflammation is an active and heterogeneous component of Alzheimer’s disease, shaped by dynamic interactions among microglia, astrocytes, neurons, and brain-interface compartments. Noncoding RNAs, including microRNAs, long noncoding RNAs, circular RNAs, and emerging small-RNA species, regulate innate immune sensing, interferon responses, phagocytosis, metabolic adaptation, inflammasome activity, and neuronal stress. Their effects are strongly context dependent: the same noncoding RNA can exert different or even opposing functions according to cell identity, intracellular or extracellular localization, disease stage, and dose. Extracellular vesicles and extracellular RNA sensing further extend noncoding RNA activity beyond cell-autonomous regulation, creating intercellular circuits that couple neuronal stress to glial immune states. Noncoding RNA-regulated inflammation intersects with amyloid-β production and clearance, tau-associated stress, synaptic dysfunction, mitochondrial impairment, and regulated cell death. Rather than acting as isolated inflammatory switches, noncoding RNAs appear to tune the strength of pathological feedback networks that determine whether proteotoxic and inflammatory stress is contained or progressively amplified. The translational value of individual noncoding RNAs depends on the convergence of causal evidence, mechanistic resolution, human relevance, and therapeutic tractability. Human brain, cerebrospinal fluid, patient-derived extracellular vesicles, and induced pluripotent stem cell models are beginning to bridge experimental mechanism and human disease, while antisense oligonucleotides, engineered extracellular vesicles, targeted nanoparticles, and synthetic circular RNAs provide emerging therapeutic routes. Pleiotropy, cell-type specificity, disease-stage dependence, endosomal trafficking, and innate RNA sensing remain major barriers. Context-resolved noncoding RNA regulatory nodes that control defined neuroimmune states may ultimately enable precision neuroimmune reprogramming while preserving protective immune functions.