Leqembi and Kisunla don’t just reduce amyloid plaques that are implicated in Alzheimer’s disease. According to new research, the drugs boost levels of a healthy form of amyloid beta (Aβ42) protein in the brain, offering new insight into understanding the mechanism behind how the medications work.
The findings were published Wednesday in Brain.
The existing Alzheimer’s disease drugs are thought to lower amyloid plaques and produce better outcomes, but the new research shows that they may also help by increasing levels of a healthy form of Aβ42 in the brain, too.
The team evaluated data from nearly 26,000 patients who took part in 24 randomized clinical trials on Leqembi or Kinsunla (or now-discontinued Aduhelm). When these monoclonal antibody medications were associated with an increase in soluble Aβ42, the progression of Alzheimer’s disease slowed, the researchers found.
“All stories have two sides — even the one we have told ourselves about how anti-amyloid treatments work: by lowering amyloid,” Alberto Espay, MD, lead researcher and a professor of neurology at the University of Cincinnati, said in a statement. “In fact, they also raise the levels of Aβ42. Even if this is unintended, it is why there may be a benefit.”
“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,” he added.
Aβ42 is a protein that consists of 42 amino acids. The proteins can harden and bind together to form the brain tissue plaques linked with Alzheimer’s disease. In its natural state, Aβ42 shouldn’t clump together; when in a soluble state, Aβ42 plays a crucial role in maintaining the health of brain cells, the Cincinnati team explained.
“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,” Espay said.
Inflammation or infection may drive amyloid to clump into plaques, instead of flowing freely, he added.
“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.
Espay believes the monoclonal antibody drugs may not be the best way to increase Aβ42, however, because removing amyloid from the brain is toxic in the long run and may cause the brain to shrink. He is currently working on other therapies to increase soluble Aβ42 levels without targeting amyloid.
