Alzheimer’s disease begins when plaques of the protein amyloid beta build up in the brain. After years of amyloid accumulation, a second brain protein, tau, begins to form tangles that are toxic to neurons. People with Alzheimer’s begin to experience cognitive symptoms, such as memory loss, around the time tau involvement is detectable. The brain changes that lead to Alzheimer’s start slowly and silently. Up to two decades before the characteristic symptoms of memory loss and confusion appear, amyloid beta protein begins to accumulate in plaques in the brain. Tau plexuses appear later, followed by atrophy of major brain areas. This is the time when people show unmistakable signs of cognitive decline.
How Alzheimer’s and Insomnia are Related
Sleep disorders can be an early sign of Alzheimer’s disease. Many people diagnosed with Alzheimer’s struggle with problems falling asleep and staying asleep years before cognitive problems such as memory problems and confusion appear. It’s a vicious circle: Alzheimer’s disease involves changes in the brain that disrupt sleep, and poor sleep in turn speeds up harmful changes in the brain. Previous research, published in Science Translational Medicine, has shown that elderly people in particular, who get less deep sleep—the kind of deep sleep you need to solidify memories and wake up refreshed—have higher levels of the brain protein tau, which is associated with brain damage and cognitive decline. Researchers found that total sleep amount was not associated with tau, but that slow-wave sleep (a specific sleep phase that occurs during deep sleep) reflects sleep quality, and that people with increased tau pathology actually slept more at night and napped more during the day, but not experience such a good deep sleep.
Sleeping Pills in the Fight Against Alzheimer’s
Researchers at the Washington University School of Medicine in St. Louis led by Dr. Brendan Lucey, assistant professor of neurology and director of the Washington University Sleep Medicine Center, who also participated in the earlier study, have found a possible way to break the negative cycle between Alzheimer’s and sleep quality. A recent study lasting two days showed that people who took a sleeping pill before bed experienced a drop in levels of key Alzheimer’s proteins. This is a good sign, as higher levels of such proteins are associated with worsening of the disease. The study, which involved a sleep aid called Suvorexant, already approved by the US Food and Drug Administration (FDA) for insomnia, points to the potential of sleep aids to slow or completely stop the progression of Alzheimer’s disease.The Study was published in April in the Annals of Neurology.
Suvorexant belongs to a class of drugs for insomnia known as dual orexin receptor antagonists. Orexin is a natural biomolecule that promotes wakefulness. When orexin is blocked, people fall asleep. Three orexin inhibitors have been approved by the FDA and others are in the pipeline. Lucey and colleagues were among the first to show in humans that poor sleep is associated with higher levels of amyloid and tau in the brain. The question remains whether getting good sleep has the opposite effect – reducing amyloid and tau levels and halting or reversing the progression of Alzheimer’s disease – mouse studies using orexin inhibitors have shown promise.
Lowering Dangerous Levels of Amyloid and Tau in the Brain
As a first step in evaluating the effect of orexin inhibitors on humans, Lucey and colleagues recruited 38 participants, ages 45 to 65 and without cognitive impairment, to undergo a two-night sleep study. Participants received a lower dose (10 mg) of suvorexant (13 people), a higher dose (20 mg) of suvorexant (12 people), or a placebo (13 people) at 9 p.m. They went to sleep in a clinical research unit at Washington University. The researchers removed a small amount of CSF via spinal tap every two hours for 36 hours, starting one hour before administration of the sleeping pill or placebo, to measure how amyloid and tau levels changed over the next day and a half. The levels of amyloid in the cerebrospinal fluid of people who received the high dose of Suvorexant fell by 10 to 20 percent compared to people who received a placebo, and levels of a key form of tau known as hyperphosphorylated tau fell by 10 to 15 percent, compared to people who received a placebo. Both differences are statistically significant. There was no significant difference between people who received a low dose of Suvorexant and those who received the placebo.
24 hours after the first dose, hyperphosphorylated tau levels had increased in the high dose group while amyloid levels remained low compared to the placebo group. A second dose of suvorexant, given on the second night, caused levels of both proteins to fall again in people in the high-dose group. The researchers believe that if they can lower amyloid every day, the accumulation of amyloid plaques in the brain will decrease over time.
The study is preliminary because it only looked at the effects of two doses of the drug in a small group of participants. Researchers are currently conducting studies to evaluate the longer-term effects of orexin inhibitors in people at higher risk of dementia and to find the right dosage. While more research is needed to develop drugs that could help to prevent cognitive decline in the future, early results are promising. Until then, the experts recommend taking all possible measures available to promote restful sleep.