How sleep patterns could be key to understanding Alzheimer’s progression

A pioneer in Alzheimer’s sleep research talks about this fortuitous discovery and where the research is headed

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When Elsevier released a report analyzing the past 50 years of research on Alzheimer’s disease, the results revealed a hidden cluster of articles that could indicate where research is headed: a small cohort of articles focused on the relationship between Alzheimer’s and sleep.

The number of papers – about 450 – is small relative to the tens of thousands analyzed. However, using Elsevier’s research analytics platform SciVal, which computes granular bibliometric analyses from Scopus data, our analysts identified a high level of citation activity – an indicator that interest in this area may be accelerating.

David M. Holtzman, MDProf. David Holtzman of the Department of Neurology at Washington University School of Medicine in St. Louis and founder of the Holtzman Lab has spent 25 years trying to better understand mechanisms underlying neurodegeneration, particularly as they relate to Alzheimer’s. He was one of the first to investigate the connection between Alzheimer’s and sleep and has noticed the increasing interest in the topic in recent times.

“It’s been exciting,” he said. “Historically, the scientists who work on a topic like Alzheimer’s, and the scientists who work on sleep, hadn’t been interacting very much. I’ve been invited to a lot of conferences on sleep over the last 10 years where, initially, I’d be the only person working on neurodegenerative disease.

“Over the last few years, a lot more people have been getting into the field,” he added, pointing out that that the National Institute of Aging at the NIH has put out requests for grant applications on this topic, and more grants are getting funded in general.

As well as the distress it causes its 45 million sufferers and their families, Alzheimer’s is one of the most costly diseases in Western countries, so any indication or progress in understanding it is met with a surge of interest.

“I think people have started to realize that we have some really important findings on this coming out of our lab, and from several other labs around the world,” David said. “There are still no disease-modifying treatments for Alzheimer’s, so people are very enthusiastic about research that will help deepen our knowledge.”

A fortuitous discovery

When David first began studying Alzheimer’s 26 years ago, he focused on the basic mechanisms of the disease. He stumbled onto the sleep connection unexpectedly:

In around 2007, we were exploring basic neural mechanisms in the brain that regulate amyloid beta – one of the proteins involved in Alzheimer’s. What we found is that we had developed a technique to measure this protein nearly in real time in the brains of mice. We found that levels of this protein were fluctuating during the day and night, and we didn’t understand why.

When we started figuring it out, we realized that the amyloid protein is higher during wakefulness and lower during sleep. We thought that was really potentially important because the level of the protein is what ultimately determines whether it’s going to accumulate in the brain.

Further research showed that during wakefulness, global synaptic activity in the brain is higher, resulting in a higher level of amyloid beta. During slow-wave sleep, it decreased. The studies found that in animals deprived of sleep over time, the peptide would accumulate and the exacerbate the pathology of the disease.

“That was our first finding that the sleep/wake cycle might regulate the risk of getting the disease if it panned out the same way in humans as in animals,” David said.

Studies conducted since that 2007 discovery indicate that the phenomenon witnessed in animals does indeed also occur in humans, and recent research on the connection between sleep and Alzheimer’s suggests further connections:

Most recently, we found that the other major protein that accumulates in the brains of Alzheimer’s patients – the Tau protein – is also strongly regulated by the sleep cycle – even more so than the amyloid protein. That’s likely very important, as the accumulation of the Tau protein is what strongly appears to be driving the cognitive decline and Alzheimer’s disease. There’s a lot that needs to be done, but there is an indication that through this normal physiological process – sleep – we might be regulating the risk of Alzheimer’s.

Prevention is likely to be the most effective way to address Alzheimer’s, David said, because the pathology of the disease is such that by the time symptoms occur, the brain is already significantly damaged.

However, he cautions that research has yet to demonstrate that this is certainly the case – rather, it is a promising thread to follow.

New research into Alzheimer’s and sleep

One of the current studies David is working on involves following a cohort of people in late middle age who are cognitively normal.

We’re assessing biomarkers within that group’s we know whether they’re developing some of the brain changes associated with Alzheimer’s before they have any cognitive problems. We’re assessing their sleep, and we’re assessing whether that becomes abnormal as they develop the pathology but while they’re still cognitively OK. We want to determine whether we could use treatments that alter sleep patterns to slow the progression of Alzheimer’s.

Elsevier’s report on Alzheimer’s also highlighted the importance of collaboration, something David agreed was beneficial in driving progress. “Outside of this institution, there are people at John Hopkins, the University of Wisconsin, New York University, University of Pennsylvania, and a number of other institutions where we are doing some collaborations, but we’re sharing information at conferences, by email and in papers. We’re also starting a major collaboration with a group in Boston.”

“Follow the results” – wherever they lead you

Having investigated Alzheimer’s for more than a quarter century, David is aware that progress in life-changing research can be gradual. It requires patience and stamina, and his advice to researchers looking to maintain their resolve in such areas is to focus on the research itself and follow the findings.

Whatever you’re working on, follow the results, because for us, it was the results that led us to understand that we needed to look at something we hadn’t been working on. Once you get some findings, don’t be afraid to learn about a new field. When we first made some findings that indicated that sleep may be a factor in the development of Alzheimer’s, if we hadn’t worked with other labs and learned how to do sleep research, we never would have made these important findings.

I think a lot of people will make a finding, but not be willing to branch out of the area they’re comfortable with. But you can’t be satisfied with that – if you make a finding, you have to be willing to follow it.

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