By Marina Zhang
For over 30 years, the amyloid hypothesis has postulated that the accumulation of amyloid beta proteins drives Alzheimer’s disease. However, a new study challenges this theory and suggests a paradigm shift in our understanding of the disease.
Aβ42, a type of amyloid beta protein, which aggregates in Alzheimer’s disease, may actually prevent cognitive decline, a new study suggests.
The study, which reviewed 24 clinical trials on 10 Alzheimer’s disease drugs, found that drugs that increased levels of Aβ42 after treatment were associated with slower cognitive impairment and clinical decline.
AΒ42 is a normal protein found throughout the brain, but its levels drop in people with dementia, Dr. Alberto Espay, professor of neurology at the University of Cincinnati College of Medicine and the study’s senior author, told The Epoch Times.
Aβ42 in brain fluids are different from Aβ42 that may get stuck in amyloid plaques, Espay said.
Effective Alzheimer’s disease drugs, including recently approved monoclonal antibodies, increase Aβ42 in brain fluids.
Drugs Increase an Amyloid Protein
Alzheimer’s disease drugs that slowed down cognitive decline were all associated with an increase in AΒ42 levels in brain fluids, the study authors found.
“Aβ42 is the normal protein, amyloid is what happens when Aβ42 clumps together,” he said.
Apart from Aβ42, various amyloid proteins and components can aggregate together to form amyloid plaques in Alzheimer’s disease. Once Aβ42 clumps together to form plaques, they are no longer functional.
The authors evaluated clinical data on monoclonal antibodies that have been recently approved by the U.S. Food and Drug Administration to treat Alzheimer’s disease. These antibodies work by breaking down amyloid plaques in the brain.
The study focused on drugs like lecanemab and donanemab which exhibited a moderate slowdown of cognitive decline in clinical trials. Both drugs, however, are associated with serious health risks and can increase the likelihood of brain swelling and brain bleeds.
The authors also evaluated clinical data on drugs that are not yet approved.
Their investigation showed that these treatments both reduced amyloid plaques and increased Aβ42 dissolved in brain and spinal fluids. This increase was linked to slower cognitive decline.
It is not clear why these monoclonal antibodies, designed to break down amyloid plaques in the brain, would increase Aβ42 levels in brain fluids, the researchers said.
Espay said that future treatment should focus on increasing Aβ42 levels. Merely reducing amyloid alone may not benefit patients and can be highly toxic due to their tendency to increase brain swelling and bleeding.
Prior studies have shown that a decrease in Aβ42 levels in brain and spinal fluids is linked to cognitive decline.
“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,” Espay said in the press release. “That’s when dementia symptoms emerge.”
The authors referenced a 2019 study involving over 5,000 people, which found that 80 percent of those who have amyloid in their brain had normal cognitive function.
Espay reports a conflict of interest for having been compensated for work with other pharmaceutical companies that produce drugs for Parkinson’s disease and other non-Alzheimer’s disease.
An Alternative to the Amyloid Hypothesis?
“These findings provide an alternative to the amyloid hypothesis,” Espray said. “They suggest that the more relevant marker for brain health is Aβ42 and that its depletion is associated with the onset of dementia,” he added.
In a previous study from 2022, which Espray led, findings suggested that Aβ42 levels in the spine and brain fluids were directly predictive of the person’s cognitive abilities.
While some researchers have challenged the amyloid hypothesis, few studies have specifically aimed to show the benefits of increasing Aβ42, because doing so challenges the conventional understanding of Alzheimer’s disease, which is based on the amyloid hypothesis, Espay said.
The amyloid pathology typically associated with Alzheimer’s disease may not be directly toxic, or even indicative of disease, Fredric Manfredsson, who was not part of the study and is an associate professor of translational neuroscience at Barrow Neurological Institute, told The Epoch Times.
Regardless of its presence in disease, rather than thinking it is the amyloid that is toxic, one equally plausible alternative could be that it is the loss of Aβ42 to plaques, and thus its function, that is causing the disease, Manfredsson said.
He cited a 2022 animal study that showed that mice supplemented with soluble Aβ42 in their brain showed improvements in their cognitive function.
As Aβ42 forms aggregates in the brain to form amyloid, it could result in a de facto loss of this protein and its functional properties, potentially contributing to disease symptoms and progression, he said.
