Can open datasets help machine learning solve medical mysteries?

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Generated: 1/26/2022
Can open datasets help machine learning solve medical mysteries? A new report suggests they might help solve mysteries about what causes dementia. And one of those mysteries might be the mysterious link between Alzheimer's and sleep.

Researchers used computer models to simulate the effects of sleep disruption by testing how the brain processes information.

"This research demonstrates that the biological changes in Alzheimer's are probably related to sleep disruption," says study leader James Sleigh, a Ph.D. candidate at the University of Montreal's Institute of Biomaterials and Biomedical Engineering.

Sleep is disrupted in the brains of Alzheimer's patients and, in people who suffer from obstructive sleep apnea, a major risk factor for dementia. Sleep issues may be especially harmful to people already showing signs of Alzheimer's.

In a paper published recently in Current Biology, researchers showed that sleep deprivation increases the risk of degeneration in a protein, known as tau, which builds up inside neurons to form Alzheimer's plaques.

By changing how tau accumulates in a mouse model of Alzheimer's disease, researchers found they could induce similar sleep-related brain changes seen in Alzheimer's humans. And just in mice — not humans.

The study is the first to demonstrate a strong and direct relationship between sleep loss and the accumulation of a major risk factor for Alzheimer's. And while researchers have studied a variety of sleep problems for their association with Alzheimer's disease, the relationship has not been so clear.

"The problem with Alzheimer's is it's not one of a few things," says James Hardy, a director at the Medical Research Council's Laboratory of Molecular Biology in England. There are at least 10 major Alzheimer's risk factors, including sleep disturbance, and some could be at play in different people, Hardy says.

To understand better that link, researchers need to know which ones are most important. "If you ask me, all the theories out there at the moment are all wrong," Hardy says.

A missing link

About 5 million Americans have Alzheimer's, the most common form of dementia. For people living with the brain disease, the loss of memories and other cognitive functions such as language skills and reasoning is gradual, taking years or decades from start to finish. About 1 million Americans are newly diagnosed each year, Hardy says. As researchers seek better ways to predict, slow or even stop the disease, they have been investigating different risk factors. The most common factor is age, but Hardy says many other factors are already on the table, including obesity, sex, and some genetic risk factors.

One candidate for a risk factor is sleep disruption. "What happens in sleep disturbance is that your brain activity doesn't end at night," says Sleigh, the first author of the study. It keeps thinking, "I have something to do; what do I do next?"

Sleigh used a modeling approach called biocomplexity, or bioCharts, to simulate how sleep might make Alzheimer's tau go missing from the brain.

Sleigh and his colleagues found that in mice, sleep deprivation led to an increase in the buildup of toxic tau protein inside the brain — not much of a worry at first because this build-up is normal with age. But when the researchers changed the way that the tau protein was made in the rodents' brains, so that it was less harmful, it made the brain look more like how tau proteins form in the younger, more active brain. There, the buildup of tau was less, and the animals did not go blind or lose their memories.

"This is a new demonstration that sleep is an independent contributing factor," Sleigh said.

'Is sleep a trigger?'

The study does not shed light on whether or how sleep loss can change the course of Alzheimer's. And the researchers point out that they did not look at actual mice brains, only simulating a build-up of tau in different ways. There is no evidence to suggest that tau protein buildup in the brain starts because something stops tau from doing that.

The current research was inspired by another study, also published in Current Biology, in 2017, that links brain protein buildup to sleep disruption in mice. It shows that sleep deprivation promotes the accumulation of proteins linked to neurofibrillary tangles that are found in Alzheimer's. Mice without tangles did not accumulate brain tau in sleep-deprived conditions.

"The question is: is sleep a trigger?" said Adam Scheller, a neuroscientist working at Rockefeller University in New York who was not involved in either study. "Or is sleep a player? It is the accumulation of the proteins that it doesn't matter."

Scheller says that if it is a trigger, it is not going to be easy for researchers to tease out a link. "These papers raise a lot of issues and suggest a lot of possible approaches to address their questions."

He says his team is still studying other areas of brain health and sleep, including what genes might be affected to change the brain.

In the end, he says, the work is still just the beginning.

"With most of the risk factors there is a big, huge 'So what?' — 'This is just another way we're not going to get a handle on the issue.'" Scheller explains. "The big question is how do you really look at the problem, what really matters, and what do you do about it. We're in a place where it's really hard to figure that out."

What is important and can we change — even at an early stage?

Many researchers agree that sleep-related risk factors are likely to be among the issues scientists need to look at.

"There's the idea that you have to look at them at a genetic level because they are inherited," said Robert McCarter, chair of the Department of Neurology at the University of Texas Health Science Center at Houston and a member of the Alzheimer's Association's Medical and Scientific Advisory Council. "Then the question is what can you do about it. That's what everyone is trying to address."

His advice is to try to make the findings stick. "Once, I'd have said that sleep disturbance is not that important in the overall scheme of things," he says. "Now I'm much more excited by the potential of this. We can see in a number of ways that sleep, in addition to genetic risk factors, is also a risk factor for Alzheimer's disease. What is important and can we do something about it in the very early stages? That's my perspective now."

But he says that to the extent that sleeping is genetic and the two genes studied are not shared, then the gene is not an avenue to pursue.

The study also highlights the difficulty researchers face in trying to study brain problems because they are in constant motion. "All of us, we're trying to study it where it is happening rather than where someone is being fixed and their brain is frozen so we can look at it," McCarter says. "We're really having to struggle for the information."

James Hardy agrees. "We think that what we do here is make the point that there is lots of information we won't see because we're not capturing it," Hardy said during the recent Alzheimer's Association International Conference in Vancouver. "We've been trying to capture as much as we can but it's very hard."

'The brain is constantly changing and so what you think you're fixing may not be the same a year down the line.'"

He says the problem is that no one knows what to do about Alzheimer's at the very early stages to slow or stop the buildup of Alzheimer's proteins that are linked to it.

The Alzheimer's Association estimates that there will be 5.4 million Americans with Alzheimer's by 2026.

The study was published recently in Current Biology. The research was funded by the National Institutes of Health, the U.S. Department of Defense and the John D. and Catherine T. MacArthur Foundation.

I am not arguing about science vs belief, but rather I am saying that belief is not always bad. It is when we think we have proof.

My own personal belief is that all people can have Alzheimer's, even the elderly, because it is not a disease caused by old age so much as it is caused by our diet and environment that cause brain degradation.

I think Alzheimer's is much more common than everyone thinks. I think that if you ask people why you see many more of them losing their memory that this is something that is happening and they are experiencing it and it is happening as a side effect of aging that no one is really watching.

If they are not watching, it is because they don't want to lose their job, or because it is illegal to do so, etc.

If you believe these people are not in pain or suffering and that it is not causing anyone any kind of hardship, you are not living in reality.

Your beliefs and thoughts affect you every day of your life and the effect they have is not always positive.

Many people can not believe in the theory that a large number of people are dying of Alzheimer's because we don't want to believe it. We choose to not look at facts and truth because we fear what we cannot accept.

I just want to say that science will never and can never, prove, that people who believe that this disease is a scam are wrong. They know it is a scam, they believe that it is a scam, they know that it is a scam, and their beliefs will never change. No amount of facts and science will ever make them accept this reality.

Garett MacGowan

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