The Alzheimer’s disease (AD) drug lecanemab’s recent success in Biogen’s Phase III clinical trials might have more to do with its effect in increasing levels of soluble amyloid-beta than in decreasing amyloid plaques in the brain, the findings of a new study published in the Journal of Alzheimer’s Disease on October 4, 2022, suggests.
In the retrospective, longitudinal study, University of Cincinnati scientists Alberto Espay, MD, professor of neurology, and Andrea Sturchio, MD, adjunct research instructor, in collaboration with the Karolinska Institute in Sweden, analyzed data from 232 patients at risk of developing AD. The patients, who were part of the Dominantly Inherited Alzheimer Network (DIAN) study, had brain amyloid plaques and carried AD-causing mutations in the APP, PSEN1, or PSEN2 genes.
“One of the strongest supports to the hypothesis of amyloid toxicity was based on these mutations,” said Sturchio said. “We studied this population because it offers the most important data.”
The investigators found, elevated levels of the highly soluble, 42-amino acid-long beta-amyloid (Aβ42) in the cerebrospinal fluid (CSF) at baseline is more predictive of slower progression of clinical dementia than lower levels of brain amyloid or lower levels of phosphorylated-tau, or total tau in amyloid plaque-positive, mutation carrying individuals. The study showed patients with an Aβ42 concentration of 270 picograms per milliliter in the CSF can remain cognitively normal regardless of the buildup of amyloid plaques in their brains.
“We found that individuals already accumulating plaques in their brains who are able to generate high levels of soluble amyloid-beta have a lower risk of evolving into dementia over a three-year span,” said Espay.
Earlier research has shown, the presence of Aβ42 is associated with normal cognition in patients with insoluble amyloid plaques who are at risk for Alzheimer’s Disease.
For over a century, the buildup of amyloid plaques in the brain has been deemed the cause of AD. However, the work by Espay and his colleagues indicate the loss of soluble Aβ42 is the more likely culprit. Soluble Aβ42 in the circulation decreases when the normal protein transforms into the amyloid plaques under biological, metabolic or infectious stress.
“The paradox is that so many of us accrue plaques in our brains as we age, and yet so few of us with plaques go on to develop dementia,” said Espay. “Yet the plaques remain the center of our attention as it relates to biomarker development and therapeutic strategies.”
Past clinical studies that reduced levels of soluble amyloid-beta in patients, worsened cognition, noted Sturchio.
“I think this is probably the best proof that reducing the level of the soluble form of the protein can be toxic,” said Sturchio, first author of the report and adjunct research instructor at UC’s College of Medicine. “When done, patients have gotten worse.”
Earlier study by Espay’s team had shown that people with high levels of soluble amyloid-beta were cognitively normal irrespective of the presence of amyloid plaques in the brain, while people with low levels of soluble amyloid-beta were more likely to experience cognitive impairment. In the current study, conducted on patients with the highest risk of developing AD, the researchers found similar results as their earlier study on the general population.
“It’s only too logical, if you are detached from the biases that we’ve created for too long, that a neurodegenerative process is caused by something we lose, amyloid-beta, rather than something we gain, amyloid plaques,” Espay said. “Degeneration is a process of loss, and what we lose turns out to be much more important.”
In future studies, Espay and Sturchio will investigate the therapeutic effects of increasing the levels of soluble Aβ42 in the brain in treating AD.