The orexinergic crossroads: Bidirectional links between sleep-wake disturbances and the pathogenesis of Alzheimer's disease in the aging brain

This review examines the bidirectional relationship between sleep instability and the pathogenesis of Alzheimer's disease, with particular emphasis on the hypothalamic orexinergic system as a key mechanistic link between these processes. Emerging evidence suggests that excessive orexin signaling contributes to insomnia and sleep fragmentation and may accelerate amyloid-β and tau accumulation by impairing glymphatic clearance and activating neurotoxic pathways. Conversely, progressive neurodegeneration can impair sleep-regulatory centers in the brainstem and hypothalamus, thereby creating a vicious cycle that may hasten cognitive decline. We further discuss therapeutic strategies targeting this pathway, with a focus on dual orexin receptor antagonists and complementary medical approaches. Notably, recent preclinical findings suggest that Panax ginseng extracts may inhibit orexin signaling and reactivate autophagy through the mammalian target of rapamycin pathway, thereby attenuating neuronal damage. By synthesizing current mechanistic insights and clinical evidence, this review proposes that modulation of the orexinergic system, through pharmacological and integrative approaches, may represent a promising strategy for delaying disease progression and improving quality of life in older adults.