sleep Alzheimer's

Sleep deprivation accelerates Alzheimer's brain damage

January 24, 2019

Science Daily/Washington University School of Medicine

A study in mice and people shows that sleep deprivation causes tau levels to rise and tau tangles to spread through the brain. Tau tangles are associated with Alzheimer's disease and brain damage.

 

Poor sleep has long been linked with Alzheimer's disease, but researchers have understood little about how sleep disruptions drive the disease.

 

Now, studying mice and people, researchers at Washington University School of Medicine in St. Louis have found that sleep deprivation increases levels of the key Alzheimer's protein tau. And, in follow-up studies in the mice, the research team has shown that sleeplessness accelerates the spread through the brain of toxic clumps of tau - a harbinger of brain damage and decisive step along the path to dementia.

 

These findings, published online Jan. 24 in the journal Science, indicate that lack of sleep alone helps drive the disease, and suggests that good sleep habits may help preserve brain health.

 

"The interesting thing about this study is that it suggests that real-life factors such as sleep might affect how fast the disease spreads through the brain," said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. "We've known that sleep problems and Alzheimer's are associated in part via a different Alzheimer's protein -- amyloid beta -- but this study shows that sleep disruption causes the damaging protein tau to increase rapidly and to spread over time."

 

Tau is normally found in the brain -- even in healthy people -- but under certain conditions it can clump together into tangles that injure nearby tissue and presage cognitive decline. Recent research at the School of Medicine has shown that tau is high in older people who sleep poorly. But it wasn't clear whether lack of sleep was directly forcing tau levels upward, or if the two were associated in some other way. To find out, Holtzman and colleagues including first authors Jerrah Holth, PhD, a staff scientist, and Sarah Fritschi, PhD, a former postdoctoral scholar in Holtzman's lab, measured tau levels in mice and people with normal and disrupted sleep.

 

Mice are nocturnal creatures. The researchers found that tau levels in the fluid surrounding brain cells were about twice as high at night, when the animals were more awake and active, than during the day, when the mice dozed more frequently. Disturbing the mice's rest during the day caused daytime tau levels to double.

 

Much the same effect was seen in people. Brendan Lucey, MD, an assistant professor of neurology, obtained cerebrospinal fluid -- which bathes the brain and spinal cord -- from eight people after a normal night of sleep and again after they were kept awake all night. A sleepless night caused tau levels to rise by about 50 percent, the researchers discovered.

 

Staying up all night makes people stressed and cranky and likely to sleep in the next chance they get. While it's hard to judge the moods of mice, they, too, rebounded from a sleepless day by sleeping more later. To rule out the possibility that stress or behavioral changes accounted for the changes in tau levels, Fritschi created genetically modified mice that could be kept awake for hours at a time by injecting them with a harmless compound. When the compound wears off, the mice return to their normal sleep-wake cycle -- without any signs of stress or apparent desire for extra sleep.

 

Using these mice, the researchers found that staying awake for prolonged periods causes tau levels to rise. Altogether, the findings suggest that tau is routinely released during waking hours by the normal business of thinking and doing, and then this release is decreased during sleep allowing tau to be cleared away. Sleep deprivation interrupts this cycle, allowing tau to build up and making it more likely that the protein will start accumulating into harmful tangles.

 

In people with Alzheimer's disease, tau tangles tend to emerge in parts of the brain important for memory -- the hippocampus and entorhinal cortex -- and then spread to other brain regions. As tau tangles mushroom and more areas become affected, people increasingly struggle to think clearly.

 

To study whether the spread of tau tangles is affected by sleep, the researchers seeded the hippocampi of mice with tiny clumps of tau and then kept the animals awake for long periods each day. A separate group of mice also was injected with tau tangles but was allowed to sleep whenever they liked. After four weeks, tau tangles had spread further in the sleep-deprived mice than their rested counterparts. Notably, the new tangles appeared in the same areas of the brain affected in people with Alzheimer's.

 

"Getting a good night's sleep is something we should all try to do," Holtzman said. "Our brains need time to recover from the stresses of the day. We don't know yet whether getting adequate sleep as people age will protect against Alzheimer's disease. But it can't hurt, and this and other data suggest that it may even help delay and slow down the disease process if it has begun."

 

The researchers also found that disrupted sleep increased release of synuclein protein, a hallmark of Parkinson's disease. People with Parkinson's -- like those with Alzheimer's -- often have sleep problems.

https://www.sciencedaily.com/releases/2019/01/190124141536.htm

Lack of sleep may be linked to risk factor for Alzheimer's disease

Preliminary study shows increased levels of beta-amyloid

April 13, 2018

Science Daily/NIH/National Institute on Alcohol Abuse and Alcoholism

Losing just one night of sleep led to an immediate increase in beta-amyloid, a protein in the brain associated with Alzheimer's disease, according to a small, new study.

 

While acute sleep deprivation is known to elevate brain beta-amyloid levels in mice, less is known about the impact of sleep deprivation on beta-amyloid accumulation in the human brain. The study is among the first to demonstrate that sleep may play an important role in human beta-amyloid clearance.

 

"This research provides new insight about the potentially harmful effects of a lack of sleep on the brain and has implications for better characterizing the pathology of Alzheimer's disease," said George F. Koob, Ph.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, which funded the study.

 

Beta-amyloid is a metabolic waste product present in the fluid between brain cells. In Alzheimer's disease, beta-amyloid clumps together to form amyloid plaques, negatively impacting communication between neurons.

 

Led by Drs. Ehsan Shokri-Kojori and Nora D. Volkow of the NIAAA Laboratory of Neuroimaging, the study is now online in the Proceedings of the National Academy of Sciences. Dr. Volkow is also the director of the National Institute on Drug Abuse at NIH.

 

To understand the possible link between beta-amyloid accumulation and sleep, the researchers used positron emission tomography (PET) to scan the brains of 20 healthy subjects, ranging in age from 22 to 72, after a night of rested sleep and after sleep deprivation (being awake for about 31 hours). They found beta-amyloid increases of about 5 percent after losing a night of sleep in brain regions including the thalamus and hippocampus, regions especially vulnerable to damage in the early stages of Alzheimer's disease.

 

In Alzheimer's disease, beta-amyloid is estimated to increase about 43 percent in affected individuals relative to healthy older adults. It is unknown whether the increase in beta-amyloid in the study participants would subside after a night of rest.

 

The researchers also found that study participants with larger increases in beta-amyloid reported worse mood after sleep deprivation.

 

"Even though our sample was small, this study demonstrated the negative effect of sleep deprivation on beta-amyloid burden in the human brain. Future studies are needed to assess the generalizability to a larger and more diverse population," said Dr. Shokri-Kojori.

 

It is also important to note that the link between sleep disorders and Alzheimer's risk is considered by many scientists to be "bidirectional," since elevated beta-amyloid may also lead to sleep disturbances.

https://www.sciencedaily.com/releases/2018/04/180413155301.htm

Sleep, Alzheimer's link explained

July 10, 2017

Science Daily/Washington University in St. Louis

Disrupting just one night of sleep in healthy, middle-aged adults causes an increase in a brain protein associated with Alzheimer's disease, research shows. Further, a week of poor sleep leads to an increase in another brain protein that has been linked to brain damage in Alzheimer's and other neurological diseases.

 

A good night's sleep refreshes body and mind, but a poor night's sleep can do just the opposite. A study from Washington University School of Medicine in St. Louis, Radboud University Medical Centre in the Netherlands, and Stanford University has shown that disrupting just one night of sleep in healthy, middle-aged adults causes an increase in amyloid beta, a brain protein associated with Alzheimer's disease. And a week of tossing and turning leads to an increase in another brain protein, tau, which has been linked to brain damage in Alzheimer's and other neurological diseases.

 

"We showed that poor sleep is associated with higher levels of two Alzheimer's-associated proteins," said David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor, head of the Department of Neurology and the study's senior author. "We think that perhaps chronic poor sleep during middle age may increase the risk of Alzheimer's later in life."

 

These findings, published July 10 in the journal Brain, may help explain why poor sleep has been associated with the development of dementias such as Alzheimer's.

 

More than 5 million Americans are living with Alzheimer's disease, which is characterized by gradual memory loss and cognitive decline. The brains of people with Alzheimer's are dotted with plaques of amyloid beta protein and tangles of tau protein, which together cause brain tissue to atrophy and die. There are no therapies that have been proven to prevent, slow or reverse the course of the disease.

 

Previous studies by Holtzman, co-first author Yo-El Ju, MD, an assistant professor of neurology, and others have shown that poor sleep increases the risk of cognitive problems. People with sleep apnea, for example, a condition in which people repeatedly stop breathing at night, are at risk for developing mild cognitive impairment an average of 10 years earlier than people without the sleep disorder. Mild cognitive impairment is an early warning sign for Alzheimer's disease.

 

But it wasn't clear how poor sleep damages the brain. To find out, the researchers -- Holtzman; Ju; co-first author and graduate student Sharon Ooms of Radboud; Jurgen Claassen, MD, PhD, of Radboud; Emmanuel Mignot, MD, PhD, of Stanford; and colleagues -- studied 17 healthy adults ages 35 to 65 with no sleep problems or cognitive impairments. Each participant wore an activity monitor on the wrist for up to two weeks that measured how much time they spent sleeping each night.

 

After five or more successive nights of wearing the monitor, each participant came to the School of Medicine to spend a night in a specially designed sleep room. The room is dark, soundproof, climate-controlled and just big enough for one; a perfect place for sleeping, even as the participants wore headphones over the ears and electrodes on the scalp to monitor brain waves.

 

Half the participants were randomly assigned to have their sleep disrupted during the night they spent in the sleep room. Every time their brain signals settled into the slow-wave pattern characteristic of deep, dreamless sleep, the researchers sent a series of beeps through the headphones, gradually getting louder, until the participants' slow-wave patterns dissipated and they entered shallower sleep.

 

The next morning, the participants who had been beeped out of slow-wave sleep reported feeling tired and unrefreshed, even though they had slept just as long as usual and rarely recalled being awakened during the night. Each underwent a spinal tap so the researchers could measure the levels of amyloid beta and tau in the fluid surrounding the brain and spinal cord.

 

A month or more later, the process was repeated, except that those who had their sleep disrupted the first time were allowed to sleep through the night undisturbed, and those who had slept uninterrupted the first time were disturbed by beeps when they began to enter slow-wave sleep.

 

The researchers compared each participant's amyloid beta and tau levels after the disrupted night to the levels after the uninterrupted night, and found a 10 percent increase in amyloid beta levels after a single night of interrupted sleep, but no corresponding increase in tau levels. However, participants whose activity monitors showed they had slept poorly at home for the week before the spinal tap showed a spike in levels of tau.

 

"We were not surprised to find that tau levels didn't budge after just one night of disrupted sleep while amyloid levels did, because amyloid levels normally change more quickly than tau levels," Ju said. "But we could see, when the participants had several bad nights in a row at home, that their tau levels had risen."

 

Slow-wave sleep is the deep sleep that people need to wake up feeling rested. Sleep apnea disrupts slow-wave sleep, so people with the disorder often wake up feeling unrefreshed, even after a full eight hours of shut-eye.

 

Slow-wave sleep is also the time when neurons rest and the brain clears away the molecular byproducts of mental activity that accumulate during the day, when the brain is busily thinking and working.

 

Ju thinks it is unlikely that a single night or even a week of poor sleep, miserable though it may be, has much effect on overall risk of developing Alzheimer's disease. Amyloid beta and tau levels probably go back down the next time the person has a good night's sleep, she said.

 

"The main concern is people who have chronic sleep problems," Ju said. "I think that may lead to chronically elevated amyloid levels, which animal studies have shown lead to increased risk of amyloid plaques and Alzheimer's."

 

Ju emphasized that her study was not designed to determine whether sleeping more or sleeping better reduce risk of Alzheimer's but, she said, neither can hurt.

 

"Many, many Americans are chronically sleep-deprived, and it negatively affects their health in many ways," Ju said. "At this point, we can't say whether improving sleep will reduce your risk of developing Alzheimer's. All we can really say is that bad sleep increases levels of some proteins that are associated with Alzheimer's disease. But a good night's sleep is something you want to be striving for anyway."

https://www.sciencedaily.com/releases/2017/07/170710161442.htm

Sleep problems may be early sign of Alzheimer's

July 5, 2017

Science Daily/American Academy of Neurology

Poor sleep may be a sign that people who are otherwise healthy may be more at risk of developing Alzheimer's disease later in life than people who do not have sleep problems, according to a study. Researchers have found a link between sleep disturbances and biological markers for Alzheimer's disease found in the spinal fluid.

 

"Previous evidence has shown that sleep may influence the development or progression of Alzheimer's disease in various ways," said study author Barbara B. Bendlin, PhD, of the University of Wisconsin-Madison. "For example, disrupted sleep or lack of sleep may lead to amyloid plaque buildup because the brain's clearance system kicks into action during sleep. Our study looked not only for amyloid but for other biological markers in the spinal fluid as well."

 

Amyloid is a protein that can fold and form into plaques. Tau is a protein that forms into tangles. These plaques and tangles are found in the brains of people with Alzheimer's disease.

 

For the study, researchers recruited 101 people with an average age of 63 who had normal thinking and memory skills but who were considered at risk of developing Alzheimer's, either having a parent with the disease or being a carrier of a gene that increases the risk for Alzheimer's disease called apolipoprotein E or APOE. Participants were surveyed about sleep quality. They also provided spinal fluid samples that were tested for biological markers of Alzheimer's disease.

 

Researchers found that people who reported worse sleep quality, more sleep problems and daytime sleepiness had more biological markers for Alzheimer's disease in their spinal fluid than people who did not have sleep problems. Those biological markers included signs of amyloid, tau and brain cell damage and inflammation.

 

"It's important to identify modifiable risk factors for Alzheimer's given that estimates suggest that delaying the onset of Alzheimer's disease in people by a mere five years could reduce the number of cases we see in the next 30 years by 5.7 million and save $367 billion in health care spending," said Bendlin.

 

While some of these relationships were strong when looking at everyone as a group, not everyone with sleep problems has abnormalities in their spinal fluid. For example, there was no link between biological markers in the spinal fluid and obstructive sleep apnea.

 

The results remained the same when researchers adjusted for other factors such as use of medications for sleep problems, amount of education, depression symptoms or body mass index.

 

"It's still unclear if sleep may affect the development of the disease or if the disease affects the quality of sleep," said Bendlin. "More research is needed to further define the relationship between sleep and these biomarkers."

 

Bendlin added, "There are already many effective ways to improve sleep. It may be possible that early intervention for people at risk of Alzheimer's disease may prevent or delay the onset of the disease."

 

One limitation of the study was that sleep problems were self-reported. Monitoring of sleep patterns by health professionals may be beneficial in future studies.

https://www.sciencedaily.com/releases/2017/07/170705164548.htm

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