Orexin and Alzheimer: A Link to Impaired Sleep

Increased orexin in this disorder is associated with disease severity, total tau protein levels, sleep impairment, and cognitive deterioration.

Orexin, a molecule that helps regulate sleep and awakening, may be disrupted in Alzheimer disease (AD), according to a recent study led by Claudio Liguori, MD, of the Sleep Medicine Centre at the University of Rome Tor Vergata.1

Also called hypocretin, orexin is a neuropeptide that regulates not only wakefulness but also purposeful activities, eating behavior, motivation, and emotional behavior. Orexin is thought to be important for maintaining a regular appetite, sleep patterns, cognitive processes, and motor control.2

The researchers compared cerebrospinal fluid (CSF) orexin levels in 48 untreated patients who had AD with those of 29 healthy controls. They also measured sleep, including total sleep time, sleep efficiency, sleep onset, rapid eye movement (REM), and non-REM sleep, as well as AD biomarkers-tau proteins and β-amyloid 1-42. The study was conducted from August 2012 to May 2013.

The 27 patients in the study with moderate to severe AD had statistically significant higher average orexin levels compared with controls and had worse sleep patterns than the controls and the 21 patients in the mild AD group. Overall, orexin increases seemed to go hand-in-hand with total tau protein levels, sleep impairment, and cognitive deterioration-as measured by the Mini-Mental State Examination.

The investigators concluded, “Our results demonstrate that, in AD, increased cerebrospinal fluid orexin levels are related to a parallel sleep deterioration, which appears to be associated with cognitive decline. Therefore, the orexinergic system seems to be dysregulated in AD, and its output and function appear to be overexpressed along the progression of the neurodegenerative process. This overexpression may result from an imbalance of the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness.”

In an editorial written in response,3 Luigi Ferini-Strambi, MD, PhD, of the Sleep Disorders Center at the Universitá Vita-Salute in Milan speculated on the next steps to be taken after this study, stating, “Further research should clarify how to modify or improve sleep for mitigating the risk of future AD or for slowing AD progression. In particular, other studies on the role of arousal, sleep alterations, and orexin in the pathogenesis of AD could suggest new preventive/therapeutic approaches.”

Direct links to AD deterioration need to be further established. Therapeutics that target orexin, to prevent AD-related decline or simply to improve sleep, may be in the works.

Key points:

• Orexin levels increase in AD.

• Increased orexin is associated with AD severity, total tau protein levels, sleep impairment, and cognitive deterioration.

• Orexin warrants further study as a therapeutic target for AD.


1. Liguori C, Romigi A, Nuccetelli M, et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol. 2014 Oct 13. doi: 10.1001/jamaneurol.2014.2510. [Epub ahead of print]

2. Clark IA, Vissel B. Inflammation-sleep interface in brain disease: TNF, insulin, orexin. J Neuroinflammation. 2014 Mar 21;11:51. doi: 10.1186/1742-2094-11-51.

3. Ferini-Strambi L. Possible role of orexin in the pathogenesis of Alzheimer disease. JAMA Neurol. 2014 Oct 13. doi: 10.1001/jamaneurol.2014.2819. [Epub ahead of print]

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