Orexinergic system bidirectionally links sleep-wake disturbances to Alzheimer's disease pathogenesis

Sleep-wake disturbances are a common and debilitating symptom in Alzheimer's disease (AD), often preceding cognitive decline. Current treatments for AD primarily address symptoms, with limited impact on disease progression, and often overlook the critical role of sleep dysregulation. The hypothalamic orexinergic system, a key regulator of arousal and sleep-wake cycles, has emerged as a crucial mechanistic link between sleep instability and AD pathology. Understanding this bidirectional relationship and targeting the orexin pathway offers a promising avenue for novel therapeutic interventions to slow AD progression.

This comprehensive review synthesized current mechanistic insights and clinical evidence on the orexinergic system's role in Alzheimer's disease and sleep-wake disturbances. Researchers examined the bidirectional relationship, focusing on how excessive orexin signaling impacts amyloid-β and tau pathology, glymphatic clearance, and neurotoxic pathways. Conversely, the review explored how progressive neurodegeneration in AD can impair sleep-regulatory centers. It also discussed therapeutic strategies, including dual orexin receptor antagonists and complementary approaches, highlighting recent preclinical findings on Panax ginseng extracts.

The review highlights that excessive orexin signaling significantly contributes to insomnia and sleep fragmentation, directly impacting Alzheimer's disease pathogenesis. This heightened signaling may accelerate the accumulation of amyloid-β and tau proteins by impairing glymphatic clearance, the brain's waste removal system, and activating neurotoxic pathways. Conversely, progressive neurodegeneration characteristic of AD can damage sleep-regulatory centers in the brainstem and hypothalamus, creating a detrimental feedback loop that exacerbates cognitive decline. This establishes a vicious cycle where sleep disturbances drive AD pathology, and AD pathology worsens sleep. > Notably, recent preclinical findings suggest that Panax ginseng extracts may inhibit orexin signaling and reactivate autophagy through the mammalian target of rapamycin (mTORC1) pathway, thereby attenuating neuronal damage. This dual action offers a potential therapeutic mechanism beyond direct orexin receptor antagonism.