The rhythm of decline: Circadian disruption inneurodegeneration
Jeewanjot Singha,* , Devinder Kumara, Jasleen Kaura, Amanpreet Singhb
a Department of Pharmacology, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab,140111, India
b Department of Pharmaceutics, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, 140111, India
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-betaaccumulation, tau hyperphosphorylation, and neuroinflammation. This review critically examines the mechanistic roleof circadian misalignment in AD by analyzing studies on sleep disturbances, SCN degeneration, metabolic dysregu-lation, clock gene polymorphisms (BMAL1, CLOCK, PER, CRY), and gut-brain axis interactions. Evidence indicates thatcircadian 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 hasbeen shown to exacerbate amyloid-beta accumulation, while tau pathology can further disrupt circadian control, creatinga vicious cycle. Dysregulated gut microbiota rhythms and associated metabolic changes further enhance neuro-inflammatory responses, increasing AD risk. Diagnostic advances such as actigraphy, melatonin assays, and plasmabiomarkers provide non-invasive methods for early detection of circadian misalignment. Therapeutic strategies targetingthe circadian systemdincluding 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.
Keywords: Alzheimer's disease, Amyloid-beta, Brain-gut axis, Circadian rhythms, Suprachiasmatic nucleus, Taupathology