The orexinergic system in Alzheimer’s disease: from sleep disruption to accelerated neurodegeneration

BACKGROUND: Sleep-wake dysregulation is increasingly recognized as an early and clinically relevant feature of Alzheimer's disease (AD), with growing evidence supporting a bidirectional relationship between disturbed sleep and AD pathophysiology. Sleep fragmentation, reduced slow-wave and REM sleep may contribute to amyloid-β (Aβ) accumulation by increasing Aβ production during wakefulness and diminishing glymphatic clearance during sleep, while emerging amyloid pathology can further disrupt sleep architecture and circadian sleep-wake rhythm, reinforcing a feed-forward cycle. SUMMARY: Within this framework, the orexinergic system, centered in the hypothalamus and crucial for arousal and sleep-wake stability, has been implicated as a mechanistic link between hyperarousal, impaired sleep consolidation, and altered amyloid dynamics. Preclinical studies suggested that orexin-A signaling can exacerbate Aβ and tau pathology and impair synaptic function, whereas biomarker studies reported high cerebrospinal fluid orexin-A levels in mild cognitive impairment and dementia due to AD. These observations raise the hypothesis that targeting orexin signaling and improving sleep may represent actionable strategies within the AD continuum. KEY MESSAGES: Clinical evidence indicates that behavioral and pharmacological interventions can improve sleep in at-risk populations, yet robust proof of disease-modifying effects on AD biomarkers or clinical progression remains limited. Ongoing trials of dual orexin receptor antagonists may clarify whether sustained modulation of sleep-wake regulation can influence AD-related biology beyond symptomatic sleep benefits.