Neuroscientist Barbara Bendlin studies the brain as Alzheimer’s disease develops. When she goes home, she tries to leave her work in the lab. But one recent research project has crossed into her personal life: She now takes sleep much more seriously.
Bendlin works at the University of Wisconsin–Madison, home to the Wisconsin Registry for Alzheimer’s Prevention, a study of more than 1,500 people who were ages 40 to 65 when they signed up. Members of the registry did not have symptoms of dementia when they volunteered, but more than 70 percent had a family history of Alzheimer’s disease.
Since 2001, participants have been tested regularly for memory loss and other signs of the disease, such as the presence of amyloid-beta, a protein fragment that can clump into sticky plaques in the brain. Those plaques are a hallmark of Alzheimer’s, the most common form of dementia.
Each person also fills out lengthy questionnaires about their lives in the hopes that one day the information will offer clues to the disease. Among the inquiries: How tired are you?
Some answers to the sleep questions have been eye-opening. Bendlin and her colleagues identified 98 people from the registry who recorded their sleep quality and had brain scans. Those who slept badly — measured by such things as being tired during the day — tended to have more A-beta plaques visible on brain imaging, the researchers reported in 2015 in Neurobiology of Aging.
In a different subgroup of 101 people willing to have a spinal tap, poor sleep was associated with biological markers of Alzheimer’s in the spinal fluid, Bendlin’s team reported last year in Neurology. The markers included some related to A-beta plaques, as well as inflammation and the protein tau, which appears in higher levels in the brains of people with Alzheimer’s.
Bendlin’s studies are part of a modest but growing body of research suggesting that a sleep-deprived brain might be more vulnerable to Alzheimer’s disease. In animal studies, levels of plaque-forming A-beta plummet during sleep. Other research suggests that a snoozing brain runs the “clean cycle” to remove the day’s metabolic debris — notably A-beta — an action that might protect against the disease. Even one sleepless night appears to leave behind an excess of the troublesome protein fragment (SN Online: 7/10/17).
But while the new research is compelling, plenty of gaps remain. There’s not enough evidence yet to know the degree to which sleep might make a difference in the disease, and study results are not consistent.
A 2017 analysis combined results of 27 studies that looked at the relationship between sleep and cognitive problems, including Alzheimer’s. Overall, poor sleepers appeared to have about a 68 percent higher risk of these disorders than those who were rested, researchers reported last year in Sleep. That said, most studies have a chicken-and-egg problem. Alzheimer’s is known to cause difficulty sleeping. If Alzheimer’s both affects sleep and is affected by it, which comes first?
For now, the direction and the strength of the cause-and-effect arrow remain unclear. But approximately one-third of U.S. adults are considered sleep deprived (getting less than seven hours of sleep a night) and Alzheimer’s is expected to strike almost 14 million U.S. adults by 2050 (5.7 million have the disease today). The research has the potential to make a big difference.
It would be easier to understand sleep deprivation if scientists had a better handle on sleep itself. The brain appears to use sleep to consolidate and process memories (SN: 6/11/16, p. 15) and to catalog thoughts from the day. But that can’t be all. Even the simplest animals need to sleep. Flies and worms sleep.
But mammals appear to be particularly dependent on sleep — even if some, like elephants and giraffes, hardly nod off at all (SN: 4/1/17, p. 10). If rats are forced to stay awake, they die in about a month, sometimes within days.
And the bodies and brains of mice change when they are kept awake, says neurologist David Holtzman of Washington University School of Medicine in St. Louis. In one landmark experiment, Holtzman toyed with mice’s sleep right when the animals’ brain would normally begin to clear A-beta. Compared with well-rested mice, sleep-deprived animals developed more than two times as many amyloid plaques over about a month, Holtzman says.
Alzheimer’s disease disrupts sleep. And disrupted sleep itself might encourage Alzheimer’s by allowing buildup of amyloid-beta, or A-beta, which is thought to lead to the death of neurons. This cycle of sleep deprivation can also affect levels of the hormone melatonin, which helps the body to sleep, and can interfere with metabolism, a disruption that is also a risk factor for Alzheimer’s.
Source: Y. Saeed and S.M. Abbott/Current Neurology and Neuroscience Reports 2017
He thinks Alzheimer’s disease is a kind of garbage collection problem. As nerve cells, or neurons, take care of business, they tend to leave their trash lying around. They throw away A-beta, which is a leftover remnant of a larger protein that is thought to form connections between neurons in the developing brain, but whose role in adults is still being studied. The body usually clears away A-beta.
But sometimes, especially when cheated on sleep, the brain doesn’t get the chance to mop up all the A-beta that the neurons produce, according to a developing consensus. A-beta starts to collect in the small seams between cells of the brain, like litter in the gutter. If A-beta piles up too much, it can accumulate into plaques that are thought to eventually lead to other problems such as inflammation and the buildup of tau, which appears to destroy neurons and lead to Alzheimer’s disease.
About a decade ago, Holtzman wanted to know if levels of A-beta in the fluid that bathes neurons fluctuated as mice ate, exercised, slept and otherwise did what mice do. It seemed like a run-of-the-mill question. To Holtzman’s surprise, time of day mattered — a lot. A-beta levels were highest when the animals were awake but fell when the mice were sleeping (SN: 10/24/09, p. 11).
“We just stumbled across this,” Holtzman says. Still, it wasn’t clear whether the difference was related to the hour, or to sleep itself. So Holtzman and colleagues designed an experiment in which they used a drug to force mice to stay awake or fall asleep. Sure enough, the A-beta levels in the brain-bathing fluid rose and fell with sleep, regardless of the time on the clock.
A-beta levels in deeply sleeping versus wide-awake mice differed by about 25 percent. That may not sound like a dramatic drop, but over the long term, “it definitely will influence the probability [that A-beta] will aggregate to form amyloid plaques,” Holtzman says.
The study turned conventional thinking on its head: Perhaps Alzheimer’s doesn’t just make it hard to sleep. Perhaps interrupted sleep drives the development of Alzheimer’s itself.
Published in Science in 2009, the paper triggered a flood of research into sleep and Alzheimer’s. While the initial experiment found that the condition worsens the longer animals are awake, research since then has found that the reverse is true, too, at least in flies and mice.
Using fruit flies genetically programmed to mimic the neurological damage of Alzheimer’s disease, a team led by researchers at Washington University School of Medicine reversed the cognitive problems of the disease by simply forcing the flies to sleep (SN: 5/16/15, p. 13).
Researchers from Germany and Israel reported in 2015 in Nature Neuroscience that slow-wave sleep — the deep sleep that occupies the brain most during a long snooze and is thought to be involved in memory storage — was disrupted in mice that had A-beta deposits in their brains. When the mice were given low doses of a sleep-inducing drug, the animals slept more soundly and improved their memory and ability to navigate a water maze.