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In both cognitively unimpaired healthy older adults and individuals with symptomatic AD, CSF orexin\u2010A is positively associated with CSF A\u03b242, p\u2010tau181, and total tau (t\u2010tau) concentrations. However, a recent systematic review and meta\u2010analysis did not support differences in orexin\u2010A between AD and controls. In this study, we tested the association between CSF orexin\u2010A concentrations, AD biomarkers, and cognitive performance in older adults with and without symptomatic AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two hundred and seventy community\u2010dwelling older adults underwent standardized cognitive assessments, sleep monitoring with a single\u2010channel electroencephalography test, one night of home sleep apnea testing, biofluid and imaging AD biomarker measurement within 1\u2009year of sleep monitoring, and <jats:italic>APOE<\/jats:italic> genotyping. Plasma and CSF AD biomarkers were measured by immunoassay or mass spectrometry. CSF orexin\u2010A was measured by radioimmunoassay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CSF orexin\u2010A levels did not differ by amyloid positivity, cognitive status, or AD stage. However, CSF AD biomarkers (A\u03b240, A\u03b242, and t\u2010tau) were positively associated with CSF orexin\u2010A levels even after correction for multiple comparisons. CSF orexin\u2010A was not associated with any measure of cognitive performance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This study showed that CSF orexin\u2010A is associated with multiple CSF AD biomarkers, but not with AD pathology or cognitive performance. We hypothesize that this is due to similar mechanisms of production\/release of these proteins with sleep\u2013wake activity. Future studies measuring other forms of orexin peptides, such as orexin\u2010B, may provide evidence for orexin as a marker for AD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70009","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T09:54:47Z","timestamp":1739786087000},"page":"780-791","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Associations of Cerebrospinal Fluid Orexin\u2010A, Alzheimer Disease Biomarkers, and Cognitive Performance"],"prefix":"10.1002","volume":"12","author":[{"given":"Ruijin","family":"Lu","sequence":"first","affiliation":[{"name":"Division of Biostatistics Washington University School of Medicine  St Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krish","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina D.","family":"Toedebusch","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Hess","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Mignot","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne E.","family":"Schindler","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St Louis Missouri USA"},{"name":"Knight Alzheimer Disease Research Center Washington University School of Medicine  St Louis Missouri USA"},{"name":"Hope Center for Neurological Disorders Washington University School of Medicine  St Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammie L. 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