Chronobiology and Neurodegeneration: The Role of Melatonin in Alzheimer's Disease

Melatonin, a hormone synthesized endogenously in the brain, exhibits a decline with advancing age and is found at reduced levels in individuals with AD. Clinical studies suggest that melatonin supplementation can enhance sleep quality, alleviate sundowning symptoms, and potentially delay the progression of cognitive deterioration in AD patients. While the precise molecular mechanisms remain under investigation, it is hypothesized that melatonin modulates the activity of various protein kinases and phosphatases involved in tau regulation. In this review, we elucidate melatonin's capacity to mitigate Aβ-induced neurotoxicity, suppress excessive microglial activation, inhibit tau protein hyperphosphorylation, and regulate insulin signaling. Additionally, melatonin contributes to reducing oxidative stress, preserving the integrity of the blood–brain barrier, supporting mitochondrial function, attenuating neuroinflammatory responses, maintaining cholinergic neurotransmission, and regulating intracellular calcium homeostasis. Thus in the current review, we aim to highlight the importance of melatonin's therapeutic potential as a multi-targeted agent in both the prevention and treatment of AD. • This review systematically consolidates evidence on melatonin's role across all major hallmarks of AD, amyloid-β neurotoxicity, production and protection, followed by its effects on tau hyperphosphorylation, mitochondrial functional dynamics, oxidative stress, calcium hypothesis, cholinergic hypothesis, neuroinflammation, blood brain barrier maintenance, insulin dynamics, circadian rhythms and concludes with its clinical and translational implications. • It advances the current understanding of melatonin as a pleiotropic molecule by positioning it within a multi-target therapeutic framework, in contrast to the reductionist focus of most existing literature on isolated mechanisms. • Despite abundant studies on melatonin's individual effects, no existing review has synthesized its actions in a unified, cross-pathological context. This review fills a significant gap by providing a holistic view of melatonin's therapeutic promise in AD.