Does improving sleep reduce signs of early Alzheimer’s disease?

The TV sitcom grandpa character who always seems to fall asleep at unfortunate moments is so common it’s almost a cliché. But daytime napping and disjointed sleep at night aren’t normal parts of aging. Sleep disturbances can be an early sign of a neurodegenerative condition, and they may be treatable.

Researchers at Washington University School of Medicine in St. Louis are launching a phase 2 clinical trial to study whether using medication to treat sleep problems in older adults can reduce signs of early Alzheimer’s. A positive result would point to a new approach to delaying or preventing the onset of Alzheimer’s dementia. The trial is supported with a $7.9 million grant from the Good Ventures Foundation, a philanthropic foundation whose mission is to help humanity thrive.

“Patients may attribute poor sleep to just getting older, but we often find that they have an underlying sleep disorder,” said principal investigator Brendan Lucey, MD, an associate professor of neurology and director of Washington University’s Sleep Medicine Center. “Chronic poor sleep may put you at risk of Alzheimer’s dementia. A major goal of our research is to find out if treating the sleep problems before people have any signs of cognitive problems can slow or even stop the progress of Alzheimer’s disease.”

Alzheimer’s disease develops slowly over the course of two decades or more. First, the protein amyloid beta starts building up into plaques in the brain. Then, a second brain protein known as tau starts collecting into toxic tangles. Soon after tangles become detectable, people start to experience memory loss and confusion. Lucey and colleagues have shown that poor sleep is linked to higher levels of both amyloid and tau in the brain.

Lucey wants to determine whether a sleep drug known as suvorexant – already approved by the Food and Drug Administration (FDA) for treatment of insomnia – can intervene to slow or delay the buildup of amyloid in the brain. Suvorexant comes from a family of drugs that suppress a protein called orexin that stimulates the brain to awaken from sleep. David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology, has shown that another member of this drug class reduces amyloid plaques in mice.

“Suvorexant has been on the market since 2014, so we know that it’s safe and well-tolerated,” Lucey said. “We plan to use the highest dose approved by the FDA in our study.”

As part of this study, Lucey and colleagues are recruiting 200 people 65 or older with difficulty sleeping and no cognitive problems to take suvorexant before bed every evening for two years. Potential participants do not need to have a diagnosed sleep condition. The researchers will use a wrist-worn accelerometer that tracks arm movement to estimate the length and quality of each participant’s sleep. Each participant will undergo a brain scan for amyloid plaques at the beginning of the study and again two years later. They will be randomly assigned to receive the drug or a placebo.

The researchers expect that the participants will vary on how they respond to the experimental therapy. To better understand the roots of such differences, Lucey, co-investigator Douglas Brubaker, PhD, an assistant professor of biomedical engineering at Purdue University, and colleagues will collect blood, cerebrospinal fluid and stool samples from participants and analyze them for differences in gene expression, protein levels, and the gut microbiome between responders and nonresponders. In addition, Brubaker will lead a separate study using mathematical modeling to investigate differences in the responses to suvorexant in cell lines and animals. Brubaker’s team will translate the results from the models to humans to better understand the role of orexin signaling in the development of Alzheimer’s disease.

This study is not designed to determine whether improving sleep prevents or delays cognitive decline. People with amyloid plaques in their brains but no cognitive symptoms are considered to be in the earliest stage of Alzheimer’s disease, years if not decades away from developing thinking problems. No cognitive benefit would be seen in just two years.

But the researchers may find that amyloid in the brain stops increasing and even, ideally, starts to decrease. If so, that would represent evidence that the seemingly inexorable progression of Alzheimer’s disease can be halted, and provide a powerful reason to launch a phase 3 clinical trial to look for cognitive benefits of improving sleep, Lucey said.

“There are several other drugs in the same class as suvorexant that are making their way through clinical trials now, so there could be quite a few options on the market in a few years,” Lucey said. “If we can show that suvorexant alters amyloid accumulation in the brain, we could go very rapidly into phase 3 studies and find out whether this approach can delay or prevent dementia.”

For more information about participating, please call 314-273-6102 or email [email protected].

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