Wake‐promoting neuromodulators in Alzheimer's disease: Implications for sleep and brain clearance

Neuromodulatory subcortical systems (NSS) regulate arousal, cognition, and sleep-wake transitions through widespread influence on cortical and subcortical networks. Increasing evidence links dysfunction of these systems to the pathogenesis of Alzheimer's disease (AD). Degeneration and dysregulation of NSS occurs during the preclinical phase of AD, preceding the onset of cognitive decline. Alterations of NSS are implicated in sleep disruption and impair sleep-dependent cerebrospinal fluid (CSF) clearance via the glymphatic system, a process involved in removing amyloid beta and other neurotoxic proteins. This review synthesizes current evidence linking wake-promoting neuromodulators-norepinephrine, histamine, and orexin-to AD pathology, with an emphasis on their convergent effects on sleep regulation and brain fluid dynamics. We propose that NSS dysfunction may drive a self-reinforcing cycle of disrupted sleep, impaired glymphatic clearance, and neurodegeneration, underscoring the need to better understand this relationship to inform pharmacological interventions slowing or preventing AD.