Disturbance of sleep patterns is known to be one of the early warning signs of the development of Alzheimer’s disease, with many people diagnosed with the disease having experienced difficulty falling asleep and staying asleep years before the cognitive symptoms develop. Now, new findings from researchers at the Washington University School of Medicine have shown that Alzheimer’s disease (AD) protein levels were reduced by people taking a sleeping pill.
The investigators hope their findings can eventually be used to break a vicious cycle in the development of AD—namely that the changes in the brain related to disease development disrupt sleep, and that this lack of sleep accelerates the harmful changes in the brain. The small, two-night study, published in the journal Annals of Neurology, used an FDA approved drug called suvorexant which if often prescribed for insomnia. While more research needs to be conducted, the reduction in the protein amyloid beta observed in the study are considered a good early sign of the potential to reduce levels of the proteins that track with worsening AD.
“This is a small, proof-of-concept study. It would be premature for people who are worried about developing Alzheimer’s to interpret it as a reason to start taking suvorexant every night,” said senior author Brendan Lucey, MD, associate professor of neurology and director of Washington University’s Sleep Medicine Center. “We don’t yet know whether long-term use is effective in staving off cognitive decline, and if it is, at what dose and for whom. Still, these results are very encouraging. This drug is already available and proven safe, and now we have evidence that it affects the levels of proteins that are critical for driving Alzheimer’s disease.”
AD begins when plaques of amyloid beta begin accumulating in the brain and years of the buildup of amyloid proteins eventually result in a second brain protein, tau, forming tangles that are toxic to neurons. AD patients first start developing symptoms such as memory loss around the time these tau tangles become detectable.
Lucey and his team have published research in the past that shows poor sleep is linked to higher levels of both amyloid and tau proteins in the brain of AD patients, but the question remains to whether good sleep has a preventative effect to reduce the levels of amyloid and tau and can halt—or even reverse—the progression of AD.
The drug used in this study, suvorexant, is in a class of sleep medications called dual orexin receptor antagonists. These drugs block the natural biomolecule orexin, which is known to promote wakefulness. In short, when orexin is blocked, people fall asleep. The FDA has approved three such drugs for insomnia and others in this class are being developed. Early mouse studies for the use of orexin inhibitors have shown promise against AD.
Lucey and colleagues sought to develop early data in the use of these drugs in people by recruiting 38 people between the ages of 45 and 65 who showed no cognitive impairment for their two-night sleep study. Of this small cohort, 13 were given a 10 mg dose of suvorexant, 12 were given a 20 mg dose, and the remaining 13 were given a placebo, who then went to sleep in the clinical research unit. They withdrew small amounts of cerebrospinal fluid via spinal tap from all participants every two hours for 36 hours, beginning one hour before the drug or placebo was given and the spinal fluid was measured to determine how the Alzheimer’s disease protein levels changed over that time.
Their findings showed that amyloid levels were reduced between 10% to 20% in the group given the higher dose compared with those given placebo, while levels of the key tau protein—hyperphosphorylated tau—dropped between 10% to 15% compared with the placebo group. While there was not a significant reduction of those given the lower dose and placebo, the difference in the higher dose group to those given placebo is statistically significant.
By 24 hours after the first dose, hyperphosphorylated tau levels in the high-dose group had risen, while amyloid levels remained low compared to the placebo group. A second dose of suvorexant, administered on the second night, sent the levels of both proteins down again for people in the high-dose group.
“If we can lower amyloid every day, we think the accumulation of amyloid plaques in the brain will decrease over time,” Lucey said. “And hyperphosphorylated tau is very important in the development of Alzheimer’s disease, because it’s associated with forming tau tangles that kill neurons. If you can reduce tau phosphorylation, potentially there would be less tangle formation and less neuronal death.”
This preliminary information is encouraging, but it only examined the effects of two doses given over a very short period of time. Lucey’s lab has already begun work to find the effects of long-term use of orexin inhibitors in a group of people consider to be at higher risk of developing dementia.
“Future studies need to have people taking these drugs for months, at least, and measuring the effect on amyloid and tau over time,” Lucey said. “We’re also going to be studying participants who are older and may still be cognitively healthy, but who already have some amyloid plaques in their brains. I’m hopeful that we will eventually develop drugs that take advantage of the link between sleep and Alzheimer’s to prevent cognitive decline.”
