Two recently FDA-approved monoclonal antibody treatments for Alzheimer's disease, lecanemab (Leqembi) and donanemab (Kisunla), may exert their therapeutic effects through a mechanism beyond simply reducing amyloid plaques in the brain, according to a new study from the University of Cincinnati.
The prevailing hypothesis has been that these drugs slow Alzheimer's by reducing levels of toxic amyloid protein plaques. However, the new research indicates that Leqembi and Kisunla also boost levels of a healthy form of amyloid beta protein, known as Aβ42, even as they reduce the toxic plaque form.
The Role of Soluble Aβ42
Aβ42 is a protein composed of 42 amino acids. While it can aggregate into plaques associated with Alzheimer's, in its soluble state, Aβ42 plays a crucial role in maintaining the health of brain cells. Dr. Alberto Espay, a professor of neurology at the University of Cincinnati and lead author of the study, theorizes that the loss of soluble Aβ42 may be a key driver of Alzheimer's, rather than just plaque formation.
"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," Dr. Espay explained. He suggests that stressors like inflammation or infection may cause amyloid to clump into plaques, reducing the availability of soluble Aβ42.
Data Analysis and Findings
In the study, Dr. Espay's team analyzed data from nearly 26,000 patients enrolled in 24 randomized clinical trials involving anti-amyloid antibody treatments, including Leqembi, Kisunla, and the now-discontinued Aduhelm. The findings, published in the journal Brain, revealed that when treatment with these drugs was associated with an increase in brain levels of soluble Aβ42, the progression of Alzheimer's slowed.
"All stories have two sides -- even the one we have told ourselves about how anti-amyloid treatments work: by lowering amyloid," Dr. Espay said. "In fact, they also raise the levels of Aβ42. Even if this is unintended, it is why there may be a benefit."
Implications for Future Therapies
Despite the potential benefit of increasing Aβ42 levels, Dr. Espay cautions that using monoclonal antibody drugs to achieve this may be inefficient and potentially unsafe in the long term. He suggests that the steady removal of amyloid plaques could have toxic effects. Dr. Espay's team is now exploring alternative therapies that focus on directly boosting soluble Aβ42 levels without targeting amyloid plaques.
"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," Dr. Espay stated, highlighting the need for new therapeutic strategies.
