Alzheimer’s disease treatment and prevention research is ongoing, with scientists investigating various approaches, including medications and lifestyle interventions. Some current Alzheimer’s disease medications, such as cholinesterase inhibitors and memantine, target symptoms and cognitive function rather than directly lowering Alzheimer’s protein levels.
In a small study of healthy volunteers, two doses of an FDA-approved sleeping pill reduced levels of Alzheimer’s proteins. The study suggests that sleep medications may be able to slow or stop the progression of Alzheimer’s disease, but much more research is needed to confirm the feasibility of such an approach.
Sleep problems can be an early indicator of Alzheimer’s disease. Many people who are eventually diagnosed with Alzheimer’s begin having trouble falling and staying asleep years before cognitive problems such as memory loss and confusion appear. It’s a vicious cycle: Alzheimer’s disease causes brain changes that disrupt sleep, and poor sleep accelerates harmful brain changes.
Researchers at Washington University School of Medicine in St. Louis believe they have discovered a way to help break the cycle. A small two-night study found that people who took a sleeping pill before bed had lower levels of key Alzheimer’s proteins, which is a good sign because higher levels of such proteins are associated with worsening disease. The study, which used suvorexant, a sleeping aid already approved by the Food and Drug Administration (FDA) for insomnia, suggests that sleep medications may be able to slow or stop the progression of Alzheimer’s disease, though much more research is needed to confirm the viability of such an approach.
The findings were published in the Annals of Neurology.
This is a small proof-of-concept experiment. It would be premature for people who are concerned about developing Alzheimer’s to interpret the study’s findings as a reason to begin taking suvorexant every night.Brendan Lucey
“This is a small proof-of-concept experiment. It would be premature for people who are concerned about developing Alzheimer’s to interpret the study’s findings as a reason to begin taking suvorexant every night,” said senior author Brendan Lucey, MD, an associate professor of neurology and director of Washington University’s Sleep Medicine Center. “We don’t yet know whether long-term use prevents cognitive decline, and if so, at what dose and for whom.” Nonetheless, these findings are very encouraging. This drug is already available and safe, and we now have evidence that it affects the levels of proteins that are important in the progression of Alzheimer’s disease.”
Suvorexant is a dual orexin receptor antagonist, which is a type of insomnia medication. Orexin is a naturally occurring biomolecule that promotes alertness. People sleep when orexin is blocked. The FDA has approved three orexin inhibitors, with more in the works.
Alzheimer’s disease develops when plaques of the protein amyloid beta begin to accumulate in the brain. After years of amyloid accumulation, a second brain protein, tau, begins to form toxic tangles. Around the time tau tangles become detectable, people with Alzheimer’s disease begin to experience cognitive symptoms such as memory loss.
Lucey and colleagues were among the first to show in people that poor sleep is linked to higher levels of both amyloid and tau in the brain. The question remains as to whether good sleep has the opposite effect – a reduction in amyloid and tau levels, and a halt in or reversal of the progress of Alzheimer’s disease – but mouse studies with orexin inhibitors have been promising.
Lucey and colleagues recruited 38 participants ages 45 to 65 with no cognitive impairments to participate in a two-night sleep study as a first step in assessing the effect of orexin inhibitors on people. At 9 p.m., the participants were given a lower dose (10 mg) of suvorexant (13 people), a higher dose (20 mg) of suvorexant (12 people), or a placebo (13 people) before going to bed in a clinical research unit at Washington University. To measure how amyloid and tau levels changed over the next day and a half, researchers drew a small amount of cerebrospinal fluid via spinal tap every two hours for 36 hours, beginning one hour before the sleeping aid or placebo was administered.
Amyloid levels in the cerebrospinal fluid of people who received the high dose of suvorexant dropped 10% to 20% compared to people who received a placebo, and levels of a key form of tau known as hyperphosphorylated tau dropped 10% to 15% compared to people who received a placebo. Both variations are statistically significant. The difference between those who received a low dose of suvorexant and those who received a placebo was not statistically significant.
Hyperphosphorylated tau levels in the high-dose group had increased 24 hours after the first dose, 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.”
The research is preliminary because it only looked at the effects of two doses of the drug in a small group of people. Lucey is conducting research into the long-term effects of orexin inhibitors in people at high risk of dementia.
“Future studies should involve people taking these drugs for at least a month and measuring the effect on amyloid and tau over time,” Lucey said. “We will also study participants who are older and may still be cognitively healthy but have some amyloid plaques in their brains.” The participants in this study were healthy middle-aged people; the results may differ in an older population.