In May 2023, the journal BMC Medicine published a study from a UC Berkeley team on the relationship between deep sleep—also known as slow-wave sleep—and Alzheimer’s disease. The paper, the latest collaboration between professors William Jagust, MD, of the School of Public Health and Matt Walker, PhD, of the Department of Psychology, highlights the possibility that such sleep could be a protective factor against cognitive decline in the context of Alzheimer’s pathology. Efforts to improve sleep might therefore be a useful intervention to slow the progression of the disease, the study notes.
We spoke with Dr. Jagust about what is known regarding the causes of Alzheimer’s and how this study fits into the picture.
Wellness Letter: Can you explain the current thinking on the cause of Alzheimer’s?
Dr. William Jagust: The dominant paradigm in Alzheimer’s disease has been that a protein in the brain called beta amyloid triggers a cascade of events. This paradigm has its adherents and detractors. It’s been highly controversial, but I think it’s very persuasive overall. What this hypothesis says is that we all make this beta amyloid protein, which is a cleavage product from a larger precursor protein. But in some people, it accumulates. It’s not clear why it accumulates. There is very, very strong evidence that genetic factors play a role for some people, but in others the reasons aren’t clear. It may have to do with the fact that the beta amyloid isn’t effectively cleared out of the brain, meaning that there’s an imbalance in production and clearance.
WL: What is the current thinking about where to intervene in this process?
WJ: The main approach to date has been a traditional pharmaceutical approach—using antibodies to draw the amyloid out of the brain. But one of the factors that an increasing number of studies have pointed to is that there’s some role for sleep in this process. There’s a relationship between sleep disorders and Alzheimer’s disease. People with Alzheimer’s have sleep disorders, for sure. But sleep disorders may also be predictive of the development of Alzheimer’s disease. There’s an association between actual measures of sleep in the laboratory and amyloid in the brain. A number of papers have shown that older people who report sleep problems have more of this amyloid in the brain.
WL: So with the amyloid hypothesis, it seems that some people might be producing too much of this protein, and in other cases it’s not cleared out effectively enough?
WJ: Exactly. So regardless of precisely how this happens, the idea is that once amyloid begins to accumulate, it interacts with another protein in the brain. This second protein is called tau, and we don’t understand why this one accumulates either. This tau protein is a normal constituent of neurons. But in aging, it can be detected in abnormal and pathological forms. We can’t measure pathological tau in any appreciable amounts in people in their 50s and younger, and it’s pretty uncommon even when people are in their 60s.
But most people in their 70s and 80s have some amount of this pathological tau in their medial temporal lobe—the part of the brain that’s involved in memory. And that doesn’t seem to be much of a problem on its own. It may relate to some of the memory loss that older people experience, but for most that loss is not a big deal. When the amyloid starts to deposit, however, it appears to interact with this tau in some way that causes this pathological tau to spread throughout the brain. And once this tau is spread throughout the brain, that’s when you begin to see serious neurological problems, such as brain atrophy, or brain shrinkage. And that’s when you start to see dementia.
What this theory explains well is the fact that amyloid is pretty weakly correlated with memory. That’s been a big question about the whole hypothesis. How can amyloid be a problem if it’s not really well correlated with memory? Well, it turns out that amyloid is very strongly correlated to the amount of tau you have in the brain. And the amount of tau you have in the brain is very strongly correlated with memory. So the idea, and there’s evidence for this in both animal and human studies, is that amyloid is somehow causing this tau to spread throughout the brain and become pathological, and that’s driving the cognitive decline. That’s the amyloid hypothesis in a nutshell.
WL: Yet we still don’t really know what’s driving this amyloid accumulation?
WJ: Right. In my lab, that’s one of the things we’ve been interested in. Why do some people accumulate amyloid and others don’t? What does the amyloid do in the brain? To investigate these questions, we have a cohort of 200 or so people who we’ve been following and assessing with serial cognitive measures, PET scans for amyloid, PET scans for tau, and brain MRI scans. We’re looking at changes in their cognition over time. And it turns out that older people without cognitive problems also deposit amyloid in the brain. There’s a lot of interest in this idea that people are accumulating amyloid for a long time before they become cognitively impaired. It’s typical of many diseases that there’s an incubation period when things start to go wrong but before symptoms appear. And one of the ideas that’s been of interest for pharmaceutical companies is that maybe we should start lowering amyloid when people are cognitively normal, before they have any symptoms at all.
WL: This is where sleep might come in?
WJ: Yes. This is work we’ve been doing with Matt Walker, who’s a sleep expert in the psychology department. Matt brings in people to his sleep lab and hooks them up for an EEG and monitors their sleep. A number of years ago, we published research in Nature Neuroscience that showed that people who have sleep problems, who have less of a type of sleep called slow-wave sleep, have more amyloid in the brain. And there’s evidence that there could be a vicious cycle where the amyloid interferes with sleep, and then the less sleep you get, the more amyloid you deposit.
WL: And this line of thinking was supported by the most recent research?
WJ: With this most recent research, a postdoctoral fellow named Zsófia Zavecz was interested in this idea of why some people with amyloid accumulation develop cognitive symptoms and others don’t. She posited that it’s the amount of sleep people are getting that is protecting them from this cognitive decline. So she took our data and did an interesting analysis that looked at the relationship between slow-wave sleep and cognitive decline. And she found that, overall, the less of this slow-wave sleep people had, the more at risk they were for cognitive decline. Or conversely, the more slow-wave sleep they had, the weaker the relationship between amyloid and cognitive decline. The findings suggested that somehow sleep was responsible for attenuating the harmful effects of amyloid in the brain.
WL: Is there a practical lesson from the research at this point?
WJ: Matt has been arguing for a while that sleep is a modifiable risk factor for Alzheimer’s disease. And I think he’s right. His argument is that we should be trying to improve sleep in older people to reduce dementia risk. The next step would be to do a clinical trial incorporating this approach, and we’ve talked about that. The problem is our labs are not really geared up to doing a clinical trial, so if we pursued that, it would need to be in another setting.
WL: Can you place this approach in the larger context of Alzheimer’s research?
WJ: We’ve seen that some drugs can reduce amyloid levels, but they don’t necessarily lead to clinical improvement. Now people are looking more at lifestyle interventions. A paper from Finland that came out a few years ago used a multi-domain lifestyle intervention, where they basically threw everything at people, like exercise, social stimulation, blood pressure control, cholesterol control, changes in diet, and weight loss. The question was, if we do all this, will we improve cognition? And they found the answer to be yes. So now this has spawned a whole bunch of other studies.
None of these multi-domain lifestyle interventions, to my knowledge, actually include sleep. Although they’re measuring sleep in some of them, they’re not actually doing sleep hygiene, which I think they should. And the question is, are lifestyle interventions going to be practical? The big issue with these, besides whether they work or not, is how do you get people to do them? I think sleep is somewhere in this discussion. My personal bias is that lifestyle does have an impact. I think physical exercise is probably an extremely beneficial intervention for cognition, at least if you get to it early enough. I think once you have Alzheimer’s disease, it’s all kind of moot. But a lot of these things make sense if we can apply them early. There is a lot to be sorted out between issues of early intervention, lifestyle changes, and pharmaceutical approaches. In my view, it’s a good time to be optimistic.
