A recent study suggests that innovative monoclonal antibody treatments for Alzheimer’s could help slow cognitive decline by raising levels of a specific brain protein.
Published in the journal Brain, the study indicates that the increase in protein levels due to new Alzheimer’s medications may be just as effective in explaining the reduction in cognitive decline as the decrease in amyloid plaque levels.
In research that challenges the traditional view of how newly approved monoclonal antibodies slow cognitive decline by targeting amyloid, scientists at the University of Cincinnati discovered that an unintended rise in a crucial brain protein correlates with cognitive improvements just as strongly as amyloid clearance does.
The study, conducted by Dr. Alberto Espay and his team, was released in the journal Brain on September 11.
For many years, the dominant theory in the field held that a protein known as amyloid-beta 42 (Aβ42), composed of 42 amino acids, forms into clumps called amyloid plaques, which subsequently harm the brain and lead to Alzheimer’s disease.
Espay’s team proposes that the normal, soluble version of Aβ42 found in the brain is vital for maintaining neuron health, and that the reduction of Aβ42, rather than the accumulation of plaques, is what triggers Alzheimer’s. This includes previous findings suggesting that dementia arises not from high levels of plaques but rather from severely low levels of Aβ42.
Espay’s research indicates that the conversion of Aβ42 into plaques is likely a typical reaction of the brain to various types of stress, whether biological, metabolic, or infectious in nature.
“As we age, many of us will develop amyloid plaques in our brains, yet very few people with plaques actually go on to develop dementia,” stated Espay, who is a professor of neurology at the UC College of Medicine and heads the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute. “Despite this, plaques continue to dominate our focus in figuring out biomarkers and treatment strategies.”
Recently, a number of monoclonal antibody drugs aimed at eliminating amyloid from the brain received approval after demonstrating their ability to decrease cognitive decline in clinical studies.
Espay and his colleagues recognized that these medications accidentally led to an increase in Aβ42 levels.
“Amyloid plaques aren’t the direct cause of Alzheimer’s, but when the brain produces too much of it in response to infections, toxins, or biological shifts, it struggles to make enough Aβ42, leading to dangerously low levels,” Espay clarified. “This is when dementia symptoms begin to appear.”
The research team evaluated information from nearly 26,000 participants involved in 24 randomized clinical trials of these new antibody therapies, examining cognitive impairment and Aβ42 level changes before and after treatment. They discovered that elevated Aβ42 levels after treatment were independently linked to a slower progression of cognitive decline.
“Every narrative has two aspects — including the one we’ve frequently told about anti-amyloid treatments working by reducing amyloid levels,” explained Espay. “In reality, they also elevate Aβ42 levels. Even if this effect is unintentional, it may be the reason for observed benefits. Our findings indicate that we can forecast cognitive outcomes in anti-amyloid studies just as effectively based on Aβ42 increases as we can with amyloid decreases.”
Espay noted that these results align with his broader theory regarding Alzheimer’s origins, as higher Aβ42 levels seem to enhance cognitive function.
“If the issue in Alzheimer’s is the deficit of the protein, then boosting its levels should be advantageous, and this study confirmed that it is,” he commented. “The logic is clear: Raising Aβ42 levels to their normal range is beneficial.”
However, Espay points out that these findings create a dilemma for doctors, as amyloid removal can be harmful and may lead to faster brain shrinkage post-treatment.
“Should we administer a treatment aimed at increasing protein levels while simultaneously reducing them? I believe that the goal of raising Aβ42 doesn’t validate the approach of lowering amyloid,” Espay remarked. His research team is focused on developing therapies that explicitly enhance Aβ42 levels without targeting amyloid.
