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WASHINGTON (AP) – When researchers at the University of Kentucky compare brains donated by people with dementia, they rarely find one with only Alzheimer brand plaques and tangles – no other pity.
If they do, "we call it a unicorn," said Donna Wilcock, Alzheimer's Disease Specialist at the Center for Seniors at the University. Contrary to popular perception, "there are many changes in brain aging that lead to dementia in addition to plaques and tangles".
This hard-won lesson helps explain how scientists are rethinking Alzheimer's disease.
For years, researchers have been guided by a dominant theory, namely that getting rid of the buildup of a sticky protein called amyloid would alleviate the disease that steals the mind. Yet, medication after medication has failed. They could clean the gunk, but they do not stop the inevitable aggravation of Alzheimer's disease. Current treatments relieve symptoms only temporarily.
The new mantra: diversify.
With more money – the government had spent a record $ 2.4 billion on Alzheimer's research this year – the focus was on exploring multiple innovative ways to combat disease now considered too complex for a single solution. On the list, researchers are targeting the brain's specialized immune system, fighting inflammation, and even asking if simulating infections play a role.
Most of these new departures are in the early stages of research. It's far from clear that everything will materialize, but "the field is now much more open-minded than ever to alternative ideas," Wilcock said.
BREAKING THE LINK PLATE AND TANGLE
Nobody knows what causes Alzheimer's disease, but amyloid deposits were a first obvious suspect, easy to spot when examining brain tissue. But it turns out that the dung begins silently to accumulate 20 years before any loss of memory, and in itself, this is not enough to cause degeneration.
Some time after the appearance of the plaques, another protein called tau begins to form entanglements in the neurons, heralding cell death and memory loss.
But again, not always: autopsies show that sometimes people die with large amounts of patches and knots, while avoiding dementia.
So, something else – maybe several other things – must also play a role. One possible culprit: the unique immune cells of the brain, called microglia (my-kroh-GLEE-ah).
No surprise if you have never heard of microglia. Neurons are the stars of the brain, the nerve cells that work together to convey information as memories. Microglia are part of a different family of cells long regarded as neural support staff. But "it's becoming clear that they're much more active and playing a much bigger role," said Dr. Richard Hodes, director of the National Institute on Aging.
A microglial task is to engulf toxic proteins and cellular debris. Recently, a mutation in a gene called TREM2 was found to weaken microglia and increase the risk of Alzheimer's disease. Dr. David Holtzman, of Washington University in St. Louis, took a closer look – and said that microglia could be key to the toxicity of the amyloid-tau duo.
In human brain donation, his team found that more and more tau nodes clustered around amyloid plaques when people carried mutations of TREM2, which weakened microglia. The researchers modified the TREM2 gene in mice and seeded their brains with some human tau. Indeed, more nodes were formed next to the plaques in mice with weak microglia than in those with functional immune cells, Nature Nature recently reported.
Why? Normal microglia seem to restrict amyloid plaques, which limits damage to surrounding tissues – damage that makes it easier to catch tau, he explained.
It was known that amyloid buildup entailed entanglement of tau, "we never had a clue how it was doing so," Holtzman said. The new findings "would argue that these cells are somehow a missing link".
Separately, biotech company Alector Inc. has begun the first step of testing a drug to boost TREM2 and better activate microglia.
THE GERM CONUNDRUM
Is gum disease or herpes to blame? The idea that infections earlier in life could pave the way for Alzheimer's disease, decades later, seemed on the verge of traditional medicine, but it is attracting new attention. This sounds strange, but the germ that causes gum disease and different strains of herpes viruses have been discovered in the brain tissue affected by Alzheimer's disease.
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The question of whether the theory of germs is a valid lawsuit was the subject of lively debate at an international meeting of the Alzheimer's Association in July. Dr. Todd Golde of the University of Florida, a skeptic, warned that the mere presence of sprouts does not mean that they were at the origin of dementia – they could be a consequence.
Nevertheless, a study conducted in 2018 in Taiwan hinted that the treatment of an infection with herpes could reduce the risk of subsequent dementia. And an American study found that some herpes viruses affect the behavior of genes linked to Alzheimer's disease.
"Maybe these are just opportunistic pathogens that have room to sprout in the brains of people with Alzheimer's disease," said Benjamin Readhead of the Arizona State University, co-author of this American paper. But, "it seems at least plausible that some of these pathogens are able to act as accelerators of the disease."
A COMMON NAME
One of the commonalities among emerging theories of Alzheimer's is how the brain's immune system defends itself aggressively – and therefore the inflammation that weighs it down.
Inflammation is a normal part of the body's response to disease and injury, a method of fighting infection or healing wounds. But when the inflammation is too strong or does not go away, it's like a fire friend who harms the cells. Do not forget that some people have a lot of patches and knots but no dementia? A few years ago, Massachusetts General researchers discovered that very few inflammations surrounded any virulent accumulation in resilient brains – but the brains affected by Alzheimer's disease were numerous.
Since then, research has shown similar inflammatory effects with other forms of dementia, such as vascular dementia, in which tiny blood vessels that feed the brain are lost or blocked, and dementias caused by Lewy bodies or dementia. other toxic proteins. An increasing list of genes related to inflammatory processes may also play a role.
A handful of medications are being studied to reduce the damage caused by inflammation without negating its beneficial effects. Take these microglia, which Holtzman said "can be a double-edged sword."
In the beginning, before there is too much plaque, it may be good to put them back together. But later, a hyperactive swarm around growing plates spits inflammatory molecules.
In addition to their work with the immune system, microglia also secrete molecules that help feed neurons, noted Wilcock of Kentucky. The goal is to restore the natural balance of a healthy brain environment, she said, so that microglia "can perform its essential functions without damaging the surrounding tissues".
AMYLOID'S STILL IN THE IMAGE
All these drug flops were not a waste of time.
"Whenever there is a failure, it is absolutely clear that we are learning a lot," Emory University neurologist Allan Levey recently told the government's advisory council on the disease. ; Alzheimer's.
A lesson: timing can be important. Most of the failed anti-amyloid drugs have been tested in people who already have at least mild symptoms. Some studies to prevent memory loss are still ongoing. Several anti-tau drugs are also tested.
Another lesson: most people have a mix of different dementias, which means that they will need a variety of treatments.
"We now have an opportunity, a real opportunity, to expand and try all these ways," said Maria Carrillo, scientific leader of the Alzheimer's Association. "The triggers as we understand them are vast."
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Marilynn Marchione, chief medical editor for the AP, contributed to the writing of this report.
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