A study published in the journal Brain shows that increases in protein levels in new Alzheimer’s drugs can explain the slowing of cognitive impairment at least as well as the reduction in amyloid plaques.
In a study that challenged the idea that newly approved monoclonal antibodies reduce cognitive decline in Alzheimer’s patients by clearing amyloid, researchers at the University of Cincinnati found that unintentionally increasing levels of a crucial brain protein correlates equally well with cognitive benefits.
Led by UC’s Alberto Espay, MD, the study was published in the journal Brain on September 11.
Study background
For decades, the prevailing theory in the field has held that a protein made up of 42 amino acids called amyloid beta-42 (Aβ42) hardens into clumps called amyloid plaques, and that those plaques damage the brain and cause Alzheimer’s disease cause.
Espay and team have hypothesized that normal, soluble Aβ42 in the brain is crucial for neuron health and that the loss of Aβ42, rather than plaque buildup, is the cause of Alzheimer’s disease. This includes published research suggesting that dementia occurs not when plaque levels are high, but when Aβ42 levels fall very low.
According to Espay’s research, the transformation of Aβ42 into plaques appears to be the brain’s normal response to biological, metabolic or infectious stress.
“Most of us will build up amyloid plaques in our brains as we age, and yet very few of us with plaques develop dementia,” says Espay, professor of neurology at the UC College of Medicine and director and endowed chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute. “Yet, plaques remain the focus of our attention in the development of biomarkers and therapeutic strategies.”
Study details
Recently, several new monoclonal antibody drugs designed to clear amyloid from the brain have been approved after being shown in clinical trials to reduce cognitive decline.
Espay and his colleagues noticed that these drugs unintentionally increased levels of Aβ42.
Amyloid plaques do not cause Alzheimer’s disease, but if the brain makes too much of it while defending against infections, toxins, or biological changes, it cannot produce enough Aβ42, causing levels to drop below a critical threshold. That is when the symptoms of dementia emerge.”
Alberto Espay, MD, professor of neurology, UC College of Medicine
The team analyzed data from nearly 26,000 patients who participated in 24 randomized clinical trials of these new antibody treatments, assessing cognitive impairment and differences in Aβ42 levels before and after treatment. They found that higher levels of Aβ42 after treatment were independently associated with slower cognitive impairment and clinical decline.
“There are two sides to all stories – even the ones we’ve told ourselves about how anti-amyloid treatments work: by lowering amyloid,” Espay said. ‘In fact, they also increase levels of Aβ42. Even if unintentional, this may be why there is a benefit. Our research shows that we can predict changes in cognitive outcomes in anti-amyloid trials at least as well by increases in Aβ42 as by decreases in amyloid.”
Espay said these findings fit well with his larger hypothesis about the cause of Alzheimer’s disease, because increasing levels of Aβ42 appear to improve cognition.
“If the problem with Alzheimer’s is the loss of the normal protein, then increasing it should be beneficial, and this study has shown that to be the case,” he said. “The story makes sense: Increasing Aβ42 levels to within the normal range is desirable.”
However, Espay believes that these results also pose a puzzle to doctors, because removing amyloid from the brain is toxic and can cause the brain to shrink more quickly after treatment with antibodies.
“Do we give patients an anti-protein treatment to increase their protein levels? I think the goal, increasing Aβ42, does not justify the means, reducing amyloid,” Espay said. Therapies that directly increase Aβ42 levels without targeting amyloid are a focus of research for Espay and his group.
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Magazine reference:
Abanto, J., et al. (2024) Increase in amyloid-β42 slows cognitive and clinical decline in Alzheimer’s disease studies. Brain. doi.org/10.1093/brain/awae216.