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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\u2010dependent 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\u2010promoting neuromodulators\u2014norepinephrine, histamine, and orexin\u2014to 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\u2010reinforcing 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.<\/jats:p>","DOI":"10.1002\/alz.71298","type":"journal-article","created":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T06:07:08Z","timestamp":1773468428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Wake\u2010promoting neuromodulators in Alzheimer's disease: Implications for sleep and brain clearance"],"prefix":"10.1002","volume":"22","author":[{"given":"Taylor J.","family":"Pedersen","sequence":"first","affiliation":[{"name":"Department of Psychological &amp; Brain Sciences Washington University in St. Louis  St. Louis Missouri USA"},{"name":"Mallinckrodt Institute of Radiology Washington University School of Medicine  St. Louis 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