Orexin-A is Associated with Increases in Cerebrospinal Fluid Phosphorylated-Tau in Cognitively Normal Elderly Subjects

Sleep. 2016 Jun 1;39(6):1253-60. doi: 10.5665/sleep.5846.


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.

Keywords: Alzheimer disease; orexin-A; phosphorylated-tau; sleep.

MeSH terms

  • Aged
  • Aging / cerebrospinal fluid*
  • Aging / metabolism
  • Aging / physiology*
  • Alzheimer Disease / cerebrospinal fluid
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Apolipoprotein E4 / analysis
  • Apolipoprotein E4 / genetics
  • Biomarkers / cerebrospinal fluid
  • Cognition / physiology*
  • Educational Status
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Orexins / metabolism*
  • Peptide Fragments / cerebrospinal fluid
  • Phosphorylation
  • Regression Analysis
  • Sleep / physiology*
  • Sleep Apnea Syndromes / diagnosis
  • Sleep Apnea Syndromes / physiopathology
  • Time Factors
  • tau Proteins / cerebrospinal fluid*
  • tau Proteins / metabolism*


  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • Biomarkers
  • Orexins
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins

Associated data

  • ClinicalTrials.gov/NCT01962779