An overabundance of orexin – a protein that helps regulate normal sleep and waking – appears linked to rising tau levels in Alzheimer’s disease, according to findings published online Oct. 13 in JAMA Neurology.
Orexin levels showed a tight positive correlation with tau – a protein that correlates positively with cognitive decline in the disease – in the cerebrospinal fluid of Alzheimer’s patients, according to a study by Dr. Claudio Liguori and associates. In addition, the sleep dysregulation characteristic of Alzheimer’s patients is tightly correlated with both increased orexin and tau levels.
“Our study has shown that, in Alzheimer’s disease, increased CSF orexin levels are linked to a parallel sleep deterioration, which appears to be related to cognitive decline,” the authors wrote. “Hence, our results demonstrate that, in [Alzheimer’s], orexinergic output and function seem to be over-expressed with disease progression and severity, possibly owing to an imbalance in the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness.”
The physiologic interplay isn’t completely understood, said Dr. Ligouri of the University of Rome Tor Vergata. But since orexinergic neurons interact with cholinergic pathways, sleep impairment might be related to the damaged cholinergic feedback characteristic of Alzheimer’s, the researchers noted (JAMA Neurol. 2014 Oct. 13 [doi:10.1001/jamaneurol.2014.2510]).
The case-control study comprised 48 drug-naive Alzheimer’s patients (21 mild and 27 moderate-severe) and 29 matched controls. All patients underwent polysomnography and lumbar puncture for CSF tau, beta amyloid peptide 1-42, and orexin.
Compared with controls, patients showed the characteristic increased CSF tau and decreased amyloid levels. Patients with moderate to severe Alzheimer’s had significantly higher CSF orexin levels than did controls (154.36 pg/mL vs. 131.03 pg/mL), but the difference between controls and patients with mild disease was not significant, Dr. Ligouri and associates reported.
The patients with moderate to severe disease also displayed earlier bedtimes, reduced sleep efficiency and REM sleep, and increased wakefulness after sleep onset, compared with controls and patients with mild disease, they said.
Orexin and both total and phosphorylated tau positively correlated in those with moderate to severe disease, although beta-amyloid peptide 1-42 showed no such pattern. No such relationship was noted in patients with mild disease or in controls.
Although there were no direct connections between cognitive scores and orexin levels, increased orexin correlated directly with increased sleep onset latency and wakefulness after sleep onset, and with decreased sleep efficiency and REM time. Increased t-tau correlated with increased time in stage 1 of non-REM sleep, but decreased time in stage 3 of non-REM sleep.
Recent studies suggest that sleep plays an important role in clearing the brain of beta amyloid 1-42 fragments before they aggregate into neurotoxic plaques. “Therefore, the sleep impairment in Alzheimer’s disease could be considered an additional detrimental factor for pathologic amyloid findings, thus worsening the neurodegeneration,” Dr. Liguori and coauthors wrote.
None of the investigators had any financial disclosures.
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