Abstract
Non-coding RNAs have emerged as central regulators of gene expression in neurodegenerative diseases, offering new opportunities for diagnosis and therapy. This review synthesizes current knowledge on microRNAs, long non-coding RNAs, and circular RNAs in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, emphasizing their roles in synaptic function, proteostasis, mitochondrial biology, and neuroinflammation. We evaluate evidence supporting non-coding RNAs as circulating and tissue-based biomarkers for early detection, disease monitoring, and patient stratification, and we compare analytical platforms and biofluid sources. Mechanistic insights reveal how non-coding RNAs modulate pathogenic protein aggregation, neuronal excitability, immune cell crosstalk, and blood-brain barrier integrity. Translational efforts toward RNA-targeted interventions are reviewed, including antisense oligonucleotides, small interfering RNAs, miRNA mimics and inhibitors, circular RNA decoys, and extracellular vesicle-mediated delivery systems. We discuss pharmacological modulation, delivery challenges, safety concerns, and strategies to enhance specificity and CNS penetration. Finally, we outline emerging computational and multi-omics approaches to prioritize therapeutic targets and propose a roadmap for advancing non-coding RNA research from preclinical models to clinical trials. Addressing biological heterogeneity and delivery barriers will be pivotal to realizing the diagnostic and therapeutic promise of the non-coding transcriptome in neurodegenerative disease. Collaboration across disciplines and rigorous clinical validation are urgently needed.