Circadian rhythms and chronotherapy in Alzheimer's disease: Mechanisms and therapeutic implications

Alzheimer's disease (AD), the most prevalent form of dementia, has been increasingly associated with disruptions in circadian rhythms and sleep-wake regulation. This narrative review synthesizes recent literature on how circadian dysfunction may contribute to AD pathogenesis, biomarker profiles, and treatment response. Mechanistic studies suggest important interactions between core clock genes and neurodegenerative cascades involving oxidative stress, neuroinflammation, glial reactivity, and proteostasis. Disruptions in circadian-regulated molecular pathways, including brain and muscle ARNT-like 1 (BMAL1)-sirtuin 1 (SIRT1), nuclear factor kappa B (NF-κB)-NOD-like receptor family pyrin domain containing 3 (NLRP3), and period circadian regulator 2 (PER2)-antioxidant signaling pathways, may compromise neuronal resilience and worsen AD-related pathology. Emerging evidence also suggests distinct circadian patterns in AD-relevant biomarkers, including melatonin, cortisol, orexin, core body temperature, blood-brain barrier permeability, and glial marker oscillations. These rhythmic patterns may have diagnostic and prognostic relevance and support the need for time-aware biomarker interpretation. Chronotherapeutic strategies targeting circadian biology, including melatonin receptor agonists, light therapy, time-restricted feeding, and circadian-aligned drug delivery systems, may help improve targeted clinical endpoints in AD. This review also discusses chronoepigenetics as an emerging area in which clock-regulated epigenetic modifications may influence neurodegenerative trajectories. Future directions include next-generation chronotherapeutic targets, such as glial clocks, clock-gated inflammatory mechanisms, and systemic comorbidities with circadian modulation, including diabetes and hypertension. Overall, the available evidence supports a close association between circadian disruption and both AD pathology and therapeutic response, while also highlighting important gaps in large-scale clinical trials. This time-oriented perspective may support the development of personalized, biomarker-guided, and rhythm-informed approaches to AD care. By bridging chronobiology and neurodegeneration, this review highlights how circadian precision medicine may refine future approaches to understanding and managing AD.