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Editorial |

Possible Role of Orexin in the Pathogenesis of Alzheimer Disease

Luigi Ferini-Strambi, MD, PhD1
[+] Author Affiliations
1Sleep Disorders Center, Division of Neuroscience, Ospedale San Raffaele, Università Vita-Salute, Milan, Italy
JAMA Neurol. 2014;71(12):1478-1480. doi:10.1001/jamaneurol.2014.2819.
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Alzheimer disease (AD) is a current and growing public health problem that really has minimally effective therapies. Even a modest reduction in the risk of AD would have a tremendous public health impact. Interestingly, sleep disturbances are multifaceted and represent an early component of AD. The severity of sleep disruption appears to parallel the severity of dementia.1

Moreover, phase delay and increased nocturnal activity seem to differentiate patients with AD from patients with other types of dementia.2 The numerous studies that have shown an altered circadian rest-activity in AD seem to indicate that sleep regulation may be related to the neurobiology of AD. It is known that accumulation of intracellular neurofibrillary tangles of tau proteins and extracellular β-amyloid (Aβ) plaques (strictly associated with brain interstitial fluid levels of Aβ) plays a central role in the pathogenesis of AD.3 Some authors using in vivo microdialysis in mice showed a correlation between interstitial Aβ amount and wakefulness (sleep deprivation) or orexin infusion.4 Orexin is a neurotransmitter that plays a fundamental role in the regulation of the sleep-wake cycle by increasing arousal levels and maintaining wakefulness. In the same study, the infusion of a dual orexin receptor antagonist was associated with a decrease of interstitial fluid Aβ amount. These findings suggest that chronic sleep deprivation (and high level of orexin) can play a role in the pathogenesis of AD. However, patients with narcolepsy-cataplexy (in whom orexin is lacking) are not protected against AD.5

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