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Misfolded proteins linked to Alzheimer's and dementia found to be greater than previously thought
Last reviewed: 15.07.2025
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For decades, the history of Alzheimer's research has focused on the battle between amyloid A-beta and tau, both of which can kill neurons and interfere with the brain's ability to function. But new research suggests that these sticky plaques in the brain may not act alone.
Researchers at Johns Hopkins University have identified more than 200 types of misfolded proteins in rats that may be linked to age-related cognitive decline.
These discoveries could pave the way for the discovery of new therapeutic targets and treatments in humans that could ease the suffering of the millions of people over 65 who suffer from Alzheimer's disease, dementia or other diseases that rob them of memory and independence as they age.
“Amyloids are clumps of misshapen proteins. They’re big, ugly, and easy to see under a microscope, so it’s no surprise that they attract our attention. But we see hundreds of proteins that are misfolded in ways that don’t form amyloid clumps, and yet they seem to affect brain function,” said Stephen Fried, an assistant professor of chemistry and a protein scientist who studies how molecules in the brain change with age.
"Our research shows that amyloids are just the tip of the iceberg."
The results were published in the journal Science Advances.
To understand the molecular differences between aging brains that remain mentally sharp and those that are in decline, Fried and his team studied 17 two-year-old rats raised in the same colony. Seven rats performed poorly on memory and problem-solving tests and were considered cognitively impaired, while 10 performed as well as six-month-old rats.
The researchers then measured more than 2,500 types of proteins in the hippocampus, a part of the brain associated with spatial learning and memory.
For the first time, scientists were able to determine for a large number of proteins whether individual proteins were misshapen or misfolded, allowing the researchers to determine which proteins were misfolded in all rats and associated with aging in general, and which were misfolded only in cognitively impaired rats.
More than 200 proteins were misshapen in cognitively impaired rats but retained their shapes in cognitively healthy rats, findings that the researchers say suggest that some of these proteins contribute to cognitive decline.
Misfolded proteins can't perform the tasks needed for a cell to function properly, so cells have a natural surveillance system that identifies and destroys these "naughty" proteins. Researchers previously thought that misfolded proteins - specifically A-beta and tau - only caused problems when they clump together into amyloids.
"We think there are a lot of proteins that can fold incorrectly, not form amyloid, and still be problematic," Fried said. "And that suggests that these misshapen proteins are somehow escaping this surveillance system in the cell."
However, exactly how these misfolded proteins escape the cell's "security system" remains a mystery.
The team next plans to study the deformed proteins under high-resolution microscopes to get a more detailed picture of what their deformations look like at the molecular level.
"Many of us have experienced a loved one or relative becoming less able to perform everyday tasks that require cognitive ability," Fried said.
"Understanding what is physically happening in the brain could lead to better treatments and prevention."