Quadruple Misfolded Proteins May Be Why Alzheimer’s Trials Fail — And the Key to Future Treatments

Researchers have known for years that Alzheimer’s is likely caused by the toxic accumulation of abnormal proteins in the brain. However, a recent discovery may shed new light on why so many Alzheimer’s treatments have failed. And it may also be the key to developing new treatments that will do a much better job.

The secret? There’s not just one or two types of abnormal proteins in the brain the contribute to Alzheimer’s, but rather four of them. These quadruple misfolded proteins are such important signs of the onset of the disease that one researcher, Peter Nelson, has begun calling them “the four horsemen of the apocalypse.”

Until recently, researchers have spent most of their time focusing on the most well-known protein that influences the development of Alzheimer’s—beta-amyloid. Billions of dollars were spent on trying to figure out how to fight beta-amyloid buildup and cure Alzheimer’s, but each new treatment failed miserably.

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However, researchers are now learning more about the different types of memory diseases of the brain, each of which involve different proteins. Being better able to differentiate between these diseases and their different proteins will help researchers target the right protein for the right disease and create more effective treatments.

“Ten or 15 years ago, everybody thought that if you lose your memories and cognitive function in aging, you have this disease called Alzheimer’s disease, and there are different manifestations of the disease, but everyone has Alzheimer’s disease,” says Peter Nelson, a neuropathologist at the University of Kentucky’s Sanders-Brown Center on Aging. “It turns out there’s a lot of different diseases that affect people in aging.”

Photo: Adobe Stock/Robert Kneschke

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Nelson and his team conducted a study, published in Journal of the American Medical Association: Neurology, in which they discovered that those dementia patients whose brains contained the proteins alpha-synuclein and TDP-43 on top of beta-amyloid and tau proteins experienced a more rapid progression than those whose dementias were caused by fewer proteins.

“It’s not just Alzheimer’s disease out there,” says Erin Abner, an author of the recent study and an associate professor at the University of Kentucky’s Sanders-Brown Center on Aging and College of Public Health. “If we are developing therapies that are targeting [beta-amyloid], they are unlikely to have any effect on alpha-synuclein and TDP-43, even if they were successful in having those downstream effects on blocking the spread of tau.”

Close to one in five people who develop dementia actually have all four of the proteins mentioned above. For these people, there is currently no treatment on the market. And that means future treatments will have to target each of the proteins individually.

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“A lot of people actually get all four of these pathologies early on and they have a very swift early decline,” Nelson says. “This implies that, maybe, there’s a biological mechanism that involves all of them, and probably other proteins, misfolding like crazy and driving this bad cognitive trajectory.”

Future methods of detecting dementia will also have to be designed to detect alpha-synuclein and TDP-43 proteins in living humans.

“It’s really inspiring that we are actually grappling with the complexity of why therapeutic trials have been failing,” Nelson says. “And now we’re developing much better strategies for addressing those pathways.”

We can’t wait to see what happens with this discovery in the future! Knowing the difference between different types of dementia caused by different types of proteins building up will make a huge difference in the treatments we invent and the ways we utilize them. This research team has done some great work!

Elizabeth Nelson

Elizabeth Nelson is a wordsmith, an alumna of Aquinas College in Grand Rapids, a four-leaf-clover finder, and a grammar connoisseur. She has lived in west Michigan since age four but loves to travel to new (and old) places. In her free time, she. . . wait, what’s free time?

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