The debate about brain clearance and dementia

The neuroscience of Alzheimer’s disease – how anaesthesia works, and why does it matter? A comment by M. Nedergaard

Alzheimer’s Disease International said that it is crucial to understand the biological processes that underlie this connection in order to get new drugs for dementia. It has proved to be a difficult task in order to acquire that knowledge. For the past decade or so, there was something of a consensus around a theory that emerged from a paper1 that Nedergaard and her colleagues wrote in 2013. It was the first time that the idea that sleep purges the brain of Alzheimer’s disease was brought up. The brain does this, they say, through its glymphatic system, which includes cerebrospinal fluid and interstitial fluid.

It’s hard to do sleep studies in a controlled manner in mice and that’s one of the factors making this disagreement difficult to solution. For starters, just mounting sensors and devices on the animals can alter their behaviour. One issue is that researchers fall back on anaesthesia when they want to sleep, but that can be a problem. “Every anaesthetic has its own characteristic — some increase glymphatic flow, and some decrease it,” Nedergaard says. She thinks thatanaesthesia is outdated.

But, despite its universality, sleep remains a mysterious process. Although sleep is important for physical and mental well-being, scientists are still trying to figure out its biological rationale. Research suggests the brain needs to be re-reset periodically to keep the mind in good order, with hints that the sleep effect on the gut might also be involved.

The Great Brain Clearance and Dementia Debate: Comment on Proulx and Franks’s “Injectory of Tracerers Directly into the Brain”

Proulx and his team’s experimental design was similar to Nedergaard’s — they did not inject tracers directly into the brain, but instead into the cerebrospinal fluid4. Most of the drugs that are injected into the brain do not go into the brain. They mostly wash out towards the lymphatic system,” he says. We found out that Nedergaard didn’t consider the other pathway for the tracers when she wrote the original paper, which may have led to some misinterpretation of her data. Nedergaard rejects this critique. Her work is valid, she says, because she’s interested in following the tracers that do enter the brain.

Nedergaard wants people to understand that the controversy isn’t just about her and Franks. “There’s a whole bunch of papers showing that sleep in humans facilitates brain clearance, so it’s not just our story or our hypothesis,” she says.

This back and forth might sound intense, but there is a lot at stake — most importantly, scientists’ foundational understanding of the pathology of dementia. And this knowledge ultimately guides the treatment of neurodegenerative diseases, says Holtzman.

Franks rejects this criticism. “This comment completely ignores the critical parameter of the rate of injection,” he says. He asserts that the damage here is unlikely.

Source: The great brain clearance and dementia debate

The Great Brain Clearance and Dementia Debate: “Is Sleep Really Important?” argues Franks, according to Nedergaard

Despite anticipating such an argument, Franks admits to being taken aback. He says he felt like he was being invited to be humiliated. “It wasn’t a meeting to really discuss whether we were right. It was about public relations and politics.

The disagreement has been unusually intense. Nedergaard asked Franks, and other researchers, to a meeting in New York in December 2024 to discuss his findings. Nedergaard said that Franks’s team was invited. “And basically, everybody told them that their paper is wrong.”

Franks says it is perfectly legitimate to use innovative techniques in science, and that if new ways of looking at a phenomenon disagree with the older methods that is scientifically interesting.

The scientists who back Nedergaard and her team think it is because of the brain clearing a proteins during sleep. Some people who support Franks say they are not sure. Franks believes that the synthesis of aprotein is reduced during sleep.

The tracing materials were not dispersed during sleep. The concentration of the dye was higher during sleep than during analgesia. Franks suggests that sleep has a negative effect on clearance.

She has co-authored more than one paper in support of this explanation. The paper examined whether the drug zolpidem had an effect on brain clearance. Their data showed that the drug reduced glymphatic flow, potentially reducing the number of proteins that could be removed from the brain. That could be why the drug affects memory negatively, and gives credence to the idea that more sleep may not lower the risk of dementia if you use it for too long. “The risk for the long term is that you would accelerate the amyloid-β deposition.”

Source: The great brain clearance and dementia debate

Margaret Thatcher and the Science of Brain Clearance: The Iron Lady and the Beagles in the Early Stages of Alzheimer’s Disease

The current challenge to the brain-clearance theory has caused scientists to criticize each other, with some accusing others of being greedy and trying to end research. The tensions are running high.

The former UK prime minster Margaret Thatcher famously managed to run the country on just four hours of sleep per night. She embraced this as part of her personal brand and identity. The Iron Lady was diagnosed with Alzheimer’s disease in later life.

Birds do it. The bees do it. Even animals without nervous systems have the ability to do it. It isn’t much for babies to do it but it is enough for their parents to be upset.

Doradol – A New Class of Substituted Driftable Drugs for Inducing Sleep and Preventing Anxiety

The most common sleep disorder is insomnia. The last decade has seen the emergence of a new class of drugs that have been effective at inducing sleep but not creating anxiety or other side effects that have previously been associated with insomnia therapies. The DORA drugs are expensive and difficult to get.

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