Circadian Rhythm Disruption and Sleep Disorders in Alzheimer's Disease: Mechanistic Insights and Therapeutic...

Alzheimer's Disease (AD) is the leading cause of dementia worldwide, with significant cognitive and behavioural impairments that devastate individuals and their families. Cohort-level findings, demonstrate the broader population-level implications of Sleep and Circadian Rhythm Disruption (SCRD) in AD and underscore the need for early interventions, emphasizing the importance of timely action. However, the mechanism remains unclear. SCRD impairs the glymphatic system, which is responsible for the clearance of neurotoxic proteins such as amyloid-β and tau during slow-wave sleep, accelerating neurodegeneration. Moreover, SCRD exacerbates neuroinflammation by disrupting the circadian regulation of immune responses, mainly through the dysregulation of microglial activity and pro-inflammatory cytokine release, which further promotes neuronal damage. This review summarizes the current understanding of SCRD in AD, outlining the mechanistic links, evidence from animal models, and emerging treatments targeting SCRD in AD, as well as promising new drug targets emerging from preclinical studies. Circadian modulation may represent a novel therapeutic avenue for AD.