Could Sleep Disorders Contribute to Alzheimer’s?

by Maria Schamis Turner

November 11, 2009

Chronic sleep deprivation may contribute to the buildup in the brain of beta-amyloid plaques—the clumps of protein seen in Alzheimer’s disease—according to a new study. If verified, the findings could mean that drugs that treat insomnia and other sleep disorders might help delay the onset of Alzheimer’s.

Beta-amyloid is produced by neurons even in healthy people, but the body quickly eliminates it. Why it tends to clump and persist in Alzheimer’s remains the subject of wide-ranging research. David Holtzman and colleagues from Washington University in St. Louis, Missouri, for instance, started their experiment by measuring beta-amyloid levels in mice genetically modified to develop Alzheimer’s-like symptoms.

But they found something unexpected: the levels of the amyloid protein appeared to fluctuate daily.

“To see that over the course of a day it could change by as much as 50 percent, even 100 percent, every single day, was striking,” Holtzman says. “Once we saw that, then we really wanted to understand why.”

To find out what was causing the daily fluctuations, Holztman and his colleagues measured beta-amyloid levels while monitoring the sleep-wake cycles of the mice. They discovered that levels were higher during wakefulness than during sleep. Changing the light conditions did not affect the daily variations, indicating that it was not light exposure that was controlling the changes in beta-amyloid levels, but the sleep-wake cycle itself.

The researchers then measured the levels when the mice were forced to stay awake. Levels of the protein were significantly higher during sleep deprivation. In addition, animals that were sleep deprived for three weeks showed greater amyloid plaque formation than mice with normal sleep-wake cycles.

The research appeared online on Sept. 24 in Science.

Molecular mechanisms

Orexin is a neurochemical that regulates wakefulness and other physiological functions and may play a role in narcolepsy and other sleep disorders. Previous research has shown that levels of orexin in the brain fluctuate in a manner similar to that the researchers saw with beta-amyloid.

When Holtzman and his colleagues gave orexin injections to the mice, their amyloid-beta levels increased. When the mice were treated with an orexin inhibitor, almorexant, the levels decreased, further suggesting that orexin may play a role in mediating levels of beta-amyloid.

“Why is it that wakefulness is associated with higher levels of beta-amyloid? There are some studies that suggest that synaptic activity is higher on average during wakefulness,” Holtzman says. “We’d like to see if we can tie this story into that or not.”

Holtzman and his colleagues have previously shown that synaptic activity influences beta-amyloid levels. The researchers speculate that differences in synaptic activity between sleep and wake states may underlie the fluctuations in beta-amyloid via the orexin pathway.

Sleep on it

“The main thing this study implies is that disorders of sleep, or disorders of orexin signaling, might predispose you to get Alzheimer’s disease later in life,” Holtzman says. “And drugs that are being developed to treat to sleep disorders that target orexin receptors may be a potential way to think about preventing or delaying Alzheimer’s.”

Neuroscientist Sigrid Veasey of the University of Pennsylvania, who was not involved in the study, says the results are important. “This is probably the first study in Alzheimer’s research to actually directly link a modifiable behavior, that is your sleep time, to one of the key features of Alzheimer’s, the beta-amyloid plaques,” she says. “What ends up being the really interesting question in this is: If you took patients with early Alzheimer’s, that is mild cognitive impairment, and enhanced sleep in as healthy a way as possible, could you actually slow the progression of disease? Or would the orexin antagonist in those patients slow the progression of the disease?”

The researchers also need to study whether there are any cognitive benefits to reducing the beta-amyloid levels and associated plaques with orexin antagonists, Veasey says. In addition, while scientists have found the same daily fluctuation of beta-amyloid levels in humans, they have not yet determined if the orexin pathway also is implicated in humans.