Insomnia, late-night habits, and irregular sleep schedules may be linked to the onset of Alzheimer's disease, says a new study published online today in ScienceExpress.

Image: FlickrCreativeCommons, CraigMDennis

"Our results are preliminary evidence that sleep abnormalities midlife could put people at risk of Alzheimer's disease later," said David Holtzman, a coauthor of the study and a neurologist at the Washington University School of Medicine. The group found that the concentration of amyloid-beta, a peptide whose build-up is linked to the onset of the disease, significantly increases during periods of sleep deprivation.

Alzheimer's disease is triggered as amyloid-beta transforms from a soluble, monomeric form into oligomers, protofibrils, and fibrils that build up as plaque in the brain's interstitial fluid, damaging neurons. Jae-Eun Kang at Washington University in St. Louis and her colleagues were studying the physiological factors regulating this process when they stumbled upon the connection between sleep and Alzheimer's disease. The team had just developed a new technology that allowed them to monitor peptides in animal and human brains on an hourly basis. As the researchers tried out their new system, called amyloid-beta microdialysis, they noticed peptide levels in both mice and men increased significantly during the day and dropped at night.

After determining that light and dark exposure wasn't responsible for the variation, the researchers manipulated sleep behavior in mice to track the effects on the peptide. Mice were kept awake an additional six hours a day, during which amyloid-beta levels spiked, suggesting a link between the variations and wakefulness. Mice subjected to chronic sleep restriction - only allowed to sleep four hours a day for 21 days - had higher amyloid-beta plaque build-up in their brain than similar-aged mice with regular sleeping habits.

"We were surprised that amyloid-beta levels were fluctuating by such wide margins -- 25, 30, even 40% -- over the course of the day," said Holtzman. "Once we knew the why, we wanted to know the how -- what molecular mechanism was causing such drastic variations corresponding with the sleep cycle."

When Kang and her colleagues injected mice with orexin, a neuropeptide hormone that regulates wakefulness, amyloid-beta levels jumped significantly. The team then blocked orexin with a receptor antagonist called almorexant, which is currently being studied by pharmaceutical companies to treat insomnia, and found that it suppressed amyloid-beta levels and eliminated the natural diurnal fluctuations.

"[The study] basically shows for the first time that environmental conditions and behavior can directly affect amyloid-beta metabolism and disease onset," Christian Haas, a biochemist at the Adolf Butenandt Institute in Munich, Germany, who was not involved in the study, said in an email. It suggests that "amyloid-beta metabolism should be directly targeted in therapeutic approaches."

Kang and her colleagues found that doses of almorexant once daily for eight weeks reduced amyloid-beta plaque build up in mice. Holtzman warned, however, that years of further study are needed for researchers to determine whether the compound has potential as a therapy.

He said the researchers now plan to work with epidemiologists to connect sleep disorders and Alzheimer's disease through case studies. The team also wants to continue researching the orexin pathway. "There are two receptors, OX1 and OX2, that bind orexin," said Holtzman. "In this study, we used a dual antagonist to block both, but we would really like to find out which of these is actually modifying the molecule" and affecting amyloid-beta concentrations.


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