Osorio, RS; Ducca, EL; Wohlleber, ME; Tanzi, EB; Gumb, T; Twumasi, A; Tweardy, S; ... de Leon, MJ; + view all Osorio, RS; Ducca, EL; Wohlleber, ME; Tanzi, EB; Gumb, T; Twumasi, A; Tweardy, S; Lewis, C; Fischer, E; Koushyk, V; Cuartero-Toledo, M; Sheikh, MO; Pirraglia, E; Zetterberg, H; Blennow, K; Lu, S-E; Mosconi, L; Glodzik, L; Schuetz, S; Varga, AW; Ayappa, I; Rapoport, DM; de Leon, MJ; - view fewer (2016) Orexin-A is Associated with Increases in Cerebrospinal Fluid Phosphorylated-Tau in Cognitively Normal Elderly Subjects. Sleep , 39 (6) pp. 1253-1260. 10.5665/sleep.5846.

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Abstract

Study Objectives: To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. Methods: Subjects were recruited from multiple community sources for National Institutes of Health supported studies on normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. Results: Levels of orexin-A, amyloid beta 42 (Aβ42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 status, age, years of education, reported total sleep time, number of awakenings, apnea-hypopnea indices (AHI), excessive daytime sleepiness, and a cognitive battery were analyzed. Subjects were 69.59 ± 8.55 years of age, 57.1% were female, and 30.2% were apolipoprotein E4+. Orexin-A was positively correlated with Aβ42, P-Tau, and T-Tau. The associations between orexin-A and the AD-biomarkers were driven mainly by the relationship between orexin-A and P-Tau and were not influenced by other clinical or sleep characteristics that were available. Conclusions: Orexin-A is associated with increased P-Tau in normal elderly individuals. Increases in orexin-A and P-Tau might be a consequence of the reduction in the proportion of the deeper, more restorative slow wave sleep and rapid eye movement sleep reported with aging. Clinical Trial Registration: Clinicaltrials.gov registration number NCT01962779. Significance Orexin is a key regulator of sleep-wake homeostasis. Deposition of abnormal phosphorylated tau (P-Tau) in neurons and glia is one of the major features of Alzheimer's disease (AD). Our results show a positive association between cerebrospinal fluid (CSF) levels of orexin-A and P-Tau in a group of cognitively normal elderly. Further, this correlation was not influenced by total sleep time, number of awakenings or sleep disordered breathing. Both findings could be explained by the decrease in the proportion of deeper restorative sleep stages that is part of normal aging or, alternatively, by AD pathology causing orexin dysfunction early in the disease process. Understanding the role of orexin dysfunction in older adults might help unfold new preventive therapies for AD.

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