Alzheimer's Drugs May Work in Whole New Way, Study Finds
By Ernie Mundell HealthDay Reporter
THURSDAY, Sept. 11, 2024 -- Two monoclonal antibody treatments to slow Alzheimer's disease, lecanemab (Leqembi) and donanemab (Kisunla), have been approved by the U.S. Food and Drug Administration over the past two years.
It's thought the drugs curb Alzheimer's by reducing levels of toxic amyloid protein plaques in the brain.
But what if another neurological effect could explain the benefit?
Researchers at the University of Cincinnati have discovered that Leqembi and Kisunla boost levels of a healthy form of amyloid beta (Aβ42) protein in the brain, even as they reduce its more toxic form in amyloid plaques.
“If the problem with Alzheimer’s is the loss of the normal protein, then increasing it should be beneficial, and this study showed that it is,” explained study lead author Dr. Alberto Espay, a professor of neurology at Cincinnati.
“The story makes sense: Increasing Aβ42 levels to within the normal range is desirable," he said in a university news release.
Aβ42 is a complex protein made up of 42 amino acids, giving it its name.
Sometimes these proteins can harden and clump together to form the brain tissue plaques that have long been associated with Alzheimer's disease.
However, Aβ42 in its natural state should not do that. It is normally soluble, and when in a soluble state Aβ42 plays a crucial role in maintaining the health of brain cells, the Cincinnati team explained.
Espay's team theorized that perhaps it is the loss of soluble Aβ42 that drives Alzheimer's, not its later clumping into plaques.
Stressors, such as inflammation or infection, might drive amyloid to clump into plaques instead of roaming free to help maintain brain health.
“Most of us will accrue amyloid plaques in our brains as we age, and yet very few of us with plaques go on to develop dementia,” Espay noted.
His theory: “Amyloid plaques don’t cause Alzheimer’s, but if the brain makes too much of it while defending against infections, toxins or biological changes, it can’t produce enough Aβ42, causing its levels to drop below a critical threshold. That’s when dementia symptoms emerge.”
In the new study, Espay's team analyzed data from nearly 26,000 patients enrolled in 24 randomized clinical trials involving the new antibody treatments.
They found that when use of Leqembi or Kinsunla (or their now-discontinued predecessor, Aduhelm) was associated with a rise in brain levels of soluble Aβ42, Alzheimer's progression slowed.
“All stories have two sides -- even the one we have told ourselves about how anti-amyloid treatments work: by lowering amyloid,” Espay said. “In fact, they also raise the levels of Aβ42. Even if this is unintended, it is why there may be a benefit.”
However, according to Espay, monoclonal antibody drugs may be boosting Aβ42 in an inefficient and perhaps (in the long term) unsafe way. He believes that the steady removal of amyloid plaques from the brain could prove to be toxic in the long run.
“Do we give patients an anti-protein treatment to increase their protein levels? I think the end, increasing Aβ42, doesn’t justify the means, decreasing amyloid,” Espay said.
He said his team are currently working on alternative therapies, ones that focus on boosting soluble Aβ42 levels without targeting amyloid plaques.
The findings were published Sept 11. in the journal Brain.
Sources
- University of Cincinnati, news release, Sept. 11, 2024
Disclaimer: Statistical data in medical articles provide general trends and do not pertain to individuals. Individual factors can vary greatly. Always seek personalized medical advice for individual healthcare decisions.
© 2025 HealthDay. All rights reserved.
Posted September 2024
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