A Master Class on Sleep
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What is the main topic discussed in this episode?
Great. Thanks, Eric, for inviting me. I'm super excited.
Yeah. So let's get right into the topic. The connection between sleep and neurodegenerative disease, particularly Alzheimer's, what's your overall perspective about how they come together?
Well, I think there's two broad areas, at least that I'm aware of, in which sleep and neurodegeneration overlap. One is with Alzheimer's disease and how sleep or circadian disruption may have a two-way direction with early Alzheimer's disease pathology, where we know, obviously, once people get Alzheimer's dementia, they have a very high prevalence of sleep problems.
What is the connection between sleep and neurodegenerative diseases?
But we now know that even in the preclinical stage, meaning prior to any cognitive symptoms, people may have sleep disturbances that are detectable through a variety of means. Also, there's some evidence to suggest that having sleep disruption may promote or speed up um, the, uh, the buildup of Alzheimer's disease-related proteins like amyloid plaques and tau tangles. So, you know, in the past, say, 15, 20 years or so, there's been a lot of data, uh, you know, starting with mice in the Holtzman lab here at WashU that have really looked at the, uh, interaction between sleep and, um, Alzheimer's disease proteins. Um, And I think as time has passed and as the biomarker field in Alzheimer's disease has advanced, we're getting more and more of these data in humans as well.
So that's one large area that's, I think, of concern to many of us. The other area in which sleep and neurodegeneration overlap a lot is in synucleinopathies, and this is a group of disorders that includes Parkinson's, dementia with Lewy bodies, multiple system atrophy. We know that there's a specific sleep disorder called REM sleep behavior disorder that people who have that sleep disorder are at heightened risk of being diagnosed with one of those synucleinopathies within 5, 10 years. So we know that sleep can be a signal and sometimes a very specific signal as to neurodegenerative disease processes that may be ongoing in the brain well before symptoms occur.
All right. Well, so you made the link between the two most important neurodegenerative diseases, Alzheimer's and Parkinson's. But regarding the mechanism, is this really related to the primacy of deep sleep, the slow wave portion of sleep, or is it really other phases as well?
So I'm a sleep doctor by training. So I think that non-REM sleep and REM sleep are both important. They're like my children, right? They are important. But when it comes to at least amyloid and tau, we think that it is the slow-wave sleep, which is kind of the deep part of non-REM sleep, that's important. One experiment that we did in my lab to really drill down into which specific part of sleep is linked to amyloid is we did a study where people came in and spent two nights, at least a month apart, and we set up a closed-loop system where, you know, after they fell asleep, we were reading their brain waves, and there was an automated system where once they started getting into deep, slow-wave sleep, they would get a little beep through headphones.
And this beep would get louder and louder and louder every 10 seconds until it nudged them out of deep sleep into lighter sleep, not waking them up fully. And we did that one night. And then on a different night, we did a sham condition where we did not deprive their slow-waste sleep. And what we found out in that study is that when we look at the spinal fluid levels of amyloid, which we measure through lumbar punctures the next morning, there's a very specific correlation between how much we're able to suppress slow-wave sleep and how much amyloid beta increases. So there seems to be this very specific link between soluble amyloid beta and slow-wave sleep. That's not to say other stages of sleep aren't important.
They are. REM sleep is very important for memory formation, for emotional regulation, and so on. But when it comes to the actual... amyloid beta levels, it seems like slow-wave sleep is the main part of sleep we should be concerned about.
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