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Neurology Today:
doi: 10.1097/01.NT.0000365758.57321.d5
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New Animal Study Suggests Sleep Deprivation May Promote Alzheimer Disease Pathology

VALEO, TOM

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ARTICLE IN BRIEF

A new paper suggests that sleep deprivation could potentially augment amyloid deposition and thereby increase Alzheimer disease (AD). Outside experts said the findings could suggest a potential new therapeutic approach for AD.

Like aging, a gene for apolipoprotein E4 (APOE4) and other risk factors, sleep deprivation may promote Alzheimer disease (AD), too. But sleep deprivation may also point to novel treatments that may keep the disease at bay, investigators reported in a paper published Sept. 24 online ahead of the print edition of Science.

The researchers found elevated amyloid beta (ABeta), the protein fragment implicated in AD, in the brains of mice deprived of sleep.

Figure. DR. DAVID HO...
Figure. DR. DAVID HO...
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Senior study author David Holtzman, MD, and colleagues inserted a tiny tube into the hippocampus of mice to sample brain interstitial fluid. They determined that levels of Abeta in that region, where AD pathology occurs, rose when mice were awake and dropped when they slept. This fluctuation was linked to the sleep-wake cycle, not to differences in the level of light. They saw the same fluctuations when they sampled the CSF of 10 young, healthy human volunteers over 33 hours.

When the mice were forced to stay awake for the first six hours of a 12-hour sleep cycle, their Abeta levels rose significantly above levels recorded during the preceding, normal sleep cycle. Suspecting that the elevation might be caused by stress, the researchers administered an antagonist to a stress hormone, corticotrophin-releasing factor before sleep deprivation, but that did not significantly lower Abeta levels.

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WHAT CAUSED ELEVATION OF ABETA?

If stress was not causing the elevation of Abeta, what was? The researchers suspected that orexin, released by the hypothalamus and known to regulate sleep, might affect diurnal fluctuation of Abeta. This seemed plausible since orexin neurons project to the hippocampus, where those fluctuations were found. Modafinil (Provigil) is believed to promote wakefulness at least in part by stimulating orexin release.

When orexin-A was infused into the ventricles for six hours at the beginning of the wake cycle, levels of Abeta increased. When almorexant, an orexin receptor antagonist, was infused for 24 hours, Abeta did not rise at all during wakefulness. Removal of almorexant restored the natural diurnal fluctuation of Abeta.

When assessed over longer periods, sleep deprivation resulted in markedly increased deposits of Abeta in transgenic mice that produce amyloid precursor protein (APP), the source of Abeta in the human brain. Daily treatment with almorexant for eight weeks significantly decreased amyloid plaque formation, suggesting that orexin signaling was involved in the production of the Abeta that aggregated into plaques.

“Chronic sleep restriction accelerates [Abeta] plaque burden, while enhancing sleep via orexin receptor blockade markedly inhibits [Abeta] plaque accumulations,” the authors concluded.

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SLEEP DEPRIVATION-AD PATHOLOGY

These findings suggest that sleep deprivation may promote the pathology that causes AD, according to Dr. Holtzman, the Andrew and Gretchen P. Jones Professor and chair of the department of neurology at the Washington University School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital.

“We don't know that it's a risk factor, but that's one of the implications,” he said. “The fluctuations in amyloid peptide in the mouse brain were also found in the CSF of humans we studied. You see the same fluctuations — during wakefulness it's high, and then drops down during sleep. In humans, however, we don't know how much sleep deprivation might lead to this kind of change.”

However, he believes that clinicians might want to start treating sleep disorders more vigorously in patients in mid-life, when AD pathology is assumed to begin.

“People who are destined to get Alzheimer disease don't start to develop amyloid deposits until they're over the age of 45 or 50,” Dr. Holtzman said. “I think the vulnerable period is going to be between 45 and 65, so in that age range it's probably really important to treat sleep disorders. People who are APOE4 positive might be vulnerable at a slightly earlier period in life — maybe in their 40s instead of in their 50s.”

But it might be premature to apply these findings directly to humans, said Ronald B. Postuma, MD, assistant professor of neurology at McGill University in Montreal.

“This paper suggests a fascinating idea, namely that sleep deprivation could potentially augment amyloid deposition and thereby increase AD,” Dr. Postuma said. “However, it is too early to directly extrapolate these results to sleep disturbances in the general population.“

Other researchers are already investigating the orexin pathway in hopes of alleviating sleep difficulties. Almorexant, the drug that Dr. Holtzman and his colleagues used to block orexin, is being developed by Actelion Pharmaceuticals of Switzerland, and has entered phase 3 clinical trials.

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SLEEP SPECIALISTS COMMENT

Figure. DR. MICHAEL ...
Figure. DR. MICHAEL ...
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“I think some of the initial data (about almorexant) sounds positive,” said Michael Thorpy, MD, director of the Sleep Wake Disorders Center at Montefiore Medical Center, and associate professor of neurology at Albert Einstein College of Medicine in the Bronx, NY. “It appears to increase slow-wave sleep, and I think it has real potential, although I don't know how far along they are with the research.”

If almorexant makes it to the market as an effective sleep aid, it possibly could be considered for treatment trials in people with AD, according to John C. Morris, MD, Friedman Distinguished Professor of Neurology and a colleague of Dr. Holtzman at Washington University School of Medicine.

“This study indicates that enhancing sleep by blocking orexin receptors can notably reduce Abeta plaque formation in these transgenic mice,” Dr. Morris said. “This suggests a potential new therapeutic approach for Alzheimer disease.”

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REFERENCES

• Kang JE, Lim MM, Holtzman DM, et al. Amyloid-{beta} dynamics are regulated by orexin and the sleep-wake cycle. Science 2009; E-pub Sept. 24. 2009

©2009 American Academy of Neurology

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