Molecular mechanism linking sleep disturbances to neurodegenaration

Abstract

Sleep disturbances are increasingly recognized as both early indicators and potential contributors to the progression of neurodegenerative diseases. Disrupted sleep compromises glymphatic clearance and synaptic homeostasis, promoting the accumulation of neurotoxic proteins such as amyloid-β, tau, and α-synuclein. Concurrently, irregular sleep patterns and circadian rhythm disturbances activate neuroinflammatory pathways, including microglial activation, NF-κB signaling, and the NLR family pyrin domain containing 3 (NLRP3) inflammasome, thereby accelerating neuronal damage. Additional mechanisms, such as mitochondrial dysfunction, oxidative stress, and imbalances in neurotransmitter systems including orexin and melatonin, further reinforce the bidirectional relationship between sleep impairment and neurodegeneration. Despite these insights, critical gaps remain, particularly the absence of reliable biomarkers for simultaneously assessing sleep quality, neuroinflammation, and disease progression, as well as limited research on disorders beyond Alzheimer’s and Parkinson’s disease. Therapeutic strategies show promise, ranging from pharmacological interventions targeting inflammatory pathways to non-pharmacological approaches such as chronotherapy, light therapy, and cognitive behavioral therapy for insomnia. Emerging modalities, including RNA-based therapies targeting pathogenic proteins and artificial intelligence (AI) for early detection and personalized treatment of sleep abnormalities, offer novel opportunities for intervention. This narrative review explores the molecular mechanisms underlying sleep disturbances in neurodegenerative diseases, identifies critical gaps in current research, and discusses emerging therapeutic strategies aimed at mitigating sleep-related neurodegeneration.