The rhythm of decline: Circadian disruption in neurodegeneration.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a multifactorial etiology involving genetic, environmental, and metabolic factors. Among these, circadian rhythm disruption has emerged as a crucial but under-explored contributor to disease progression. The circadian system, regulated by the suprachiasmatic nucleus (SCN), controls essential physiological functions such as the sleep-wake cycle, metabolism, and neuroendocrine signaling. Disruption of this system has been increasingly linked to key pathological features of AD, including amyloid-beta accumulation, tau hyperphosphorylation, and neuroinflammation. This review critically examines the mechanistic role of circadian misalignment in AD by analyzing studies on sleep disturbances, SCN degeneration, metabolic dysregulation, clock gene polymorphisms (BMAL1, CLOCK, PER, CRY), and gut-brain axis interactions. Evidence indicates that circadian abnormalities manifest as reduced melatonin secretion, impaired glymphatic clearance, and altered SCN signaling, all of which contribute to neuronal dysfunction and cognitive decline. Additionally, sleep deprivation has been shown to exacerbate amyloid-beta accumulation, while tau pathology can further disrupt circadian control, creating a vicious cycle. Dysregulated gut microbiota rhythms and associated metabolic changes further enhance neuroinflammatory responses, increasing AD risk. Diagnostic advances such as actigraphy, melatonin assays, and plasma biomarkers provide non-invasive methods for early detection of circadian misalignment. Therapeutic strategies targeting the circadian system-including light therapy, melatonin supplementation, and gene-based interventions-show promise in restoring circadian homeostasis and improving cognitive outcomes. Understanding and addressing circadian disruptions may offer novel and personalized approaches for delaying or mitigating Alzheimer's disease progression, highlighting the need for further research in this direction.