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Untangling the Alzheimer's-Sleep Connection

— Researchers inch closer to learning how sleep and Alzheimer's pathology are linked

Last Updated January 2, 2020
MedpageToday
A mature woman wired up for a sleep study to measure brain waves

In January, we reported on the first of several studies this year about sleep and Alzheimer's disease pathology. The curious relationship between sleep and Alzheimer's continued to unfold throughout the year, as scientists tried to answer what Mayo Clinic researcher Ronald Petersen, MD, called a chicken-and-egg question: "Is it that your sleep is disrupted and the Alzheimer's proteins build up -- or are the Alzheimer's proteins being deposited in the brain, disrupting sleep, and that's where the cycle gets initiated?"

Two studies in January explored how sleep might be associated with Alzheimer's tau pathology. The first, led by Brendan Lucey, MD, and David Holtzman, MD, both of Washington University in St. Louis, found that older adults who had less slow-wave sleep had higher levels of brain tau.

The findings, published in , suggested that poor quality sleep in late life may signal deteriorating brain health.

"What's interesting is that we saw this inverse relationship between decreased slow wave sleep and more tau protein in people who were either cognitively normal or very mildly impaired, meaning that reduced slow wave activity may be a marker for the transition between normal and impaired," Lucey said.

The second, also by Holtzman and Lucey's team, showed that sleep deprivation caused tau levels to rise and tau tangles to spread.

In , the researchers reported that one sleepless night caused tau levels to rise acutely in both mice and humans. In mice, chronic sleeplessness drove the spread of tau tangles, suggesting sleep may have a direct protective effect on Alzheimer's pathology.

"Amyloid is important in initiating disease, but the actual damage in the brain is probably due to the accumulation of tau," Holtzman told ľֱ. "Normally, tau protein is inside cells, but there is more and more evidence suggesting that its spread to different parts of the brain is responsible for the progression of Alzheimer's disease."

Another group of researchers also looked at tau and sleep and found that cognitively unimpaired people with sleep apnea had 4.5% higher levels of tau in the entorhinal cortex than people without apnea. But which came first is unknown, noted lead researcher Diego Carvalho, MD, of the Mayo Clinic in Rochester, Minnesota, who presented the findings at the American Academy of Neurology .

"Our research results raise the possibility that sleep apnea affects tau accumulation," he said. "But it's also possible that higher levels of tau in other regions may predispose a person to sleep apnea."

Patterns and Pathology

Sleep patterns predicted amyloid and tau burden, reported Matthew Walker, PhD, of the University of California Berkeley, and co-authors, in June.

Two types of hippocampal sleep waves -- slow oscillations and sleep spindles -- are synced in young people but may become uncoordinated in old age, and this may be linked to Alzheimer's pathology, they noted in the .

When Walker's team studied cognitively normal adults, they found that the severity of impaired slow oscillation-sleep spindle coupling predicted greater medial temporal lobe tau burden. This impairment was unique and specific to tau, but not amyloid, the researchers said.

A non-REM EEG signature -- specifically, impairments in 0.6-1Hz slow-wave-activity -- predicted cortical amyloid beta, but was not tied to tau in the medial temporal lobe or any other cortical region.

Sleep changes in earlier decades of life were tied to amyloid and tau burden, Walker and colleagues added: people who reported a decline in sleep quality in their 40s and 50s had more beta-amyloid on PET scans later in life, while those who reported sleep decline in their 50s and 60s had more tau.

Wake-Promoting Neurons

More tau research emerged this summer from Lea Grinberg, MD, PhD, of the University of California San Francisco, and co-authors, whose postmortem study suggested tau may selectively destroy wake-promoting neurons in Alzheimer's, presenting a possible explanation of why excessive napping precedes clinical disease.

In brain regions that promote wakefulness, tau buildup was high and neuronal loss was significant, the team reported in . Wake-promoting neurons appeared to be extremely vulnerable to Alzheimer's but not other tauopathies: more were lost in Alzheimer's disease than in corticobasal degeneration or progressive supranuclear palsy.

The finding supports the idea that sleep dysfunction is a manifestation of Alzheimer's pathology rather than a risk factor, "opening the door to opportunities to treat the cause, rather than the symptoms," Grinberg said in an interview with ľֱ.

"It also supports the idea that early Alzheimer's disease-like changes in the brainstem are an integral part of the disease and do have clinical consequences and should not be ignored if we want to treat the disease early," she added.

Deep Sleep, Deep Cleaning?

In November, an imaging study illustrated how cerebrospinal fluid (CSF) washes in and out of the brain during slow-wave sleep, offering possible insights about sleep and Alzheimer's or other neurodegenerative diseases.

Large oscillations of CSF appeared every 20 seconds or so during sleep, and these were tightly coupled to blood flow and slow waves, reported Laura Lewis, PhD, of Boston University College of Engineering, and co-authors, who described this activity for the first time in .

"We've known for a while that there are these electrical waves of activity in the neurons," Lewis said. "Before now, we didn't realize that there are actually waves in the CSF, too."

The findings may support the hypothesis that CSF flow and slow-wave activity may help flush toxic brain proteins, she noted.

Studies in animals could test for causal relationships, Lewis and her group suggested. And because people in this study were from ages 23 to 33, the research team plans to evaluate older adults to see how blood and CSF flow during sleep might be affected by aging.