Increasing brain protein levels could slow decline in Alzheimer’s disease

A study published in the journal Brain shows that increased protein levels with new Alzheimer’s drugs may explain the slowing of cognitive impairment at least as well as the reduction in amyloid plaques.

In a study challenging the idea that recently 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 key brain protein correlates just as well with cognitive benefits.

For decades, the prevailing theory in the field held that a 42-amino acid protein called amyloid beta 42 (Aβ42) hardened into clumps called amyloid plaques, and these plaques damaged the brain, causing Alzheimer’s disease.

Led by UC Dr. Alberto Espay, the team hypothesized that the presence of normal, soluble Aβ42 in the brain is essential for neuron health and that loss of Aβ42, rather than plaque buildup, is what causes Alzheimer’s disease. This includes published research that suggests dementia occurs not when plaque levels are high but when Aβ42 levels drop 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 accumulate amyloid plaques in our brains as we age, and yet very few of us who have them develop dementia,” said Espay, professor of neurology in 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.

“However, plaques remain at the center of our attention in the development of biomarkers and therapeutic strategies.”

Recently, several new monoclonal antibody drugs designed to clear amyloid from the brain have been approved after being shown to reduce cognitive decline in clinical trials.

Espay and his colleagues noticed that these drugs unintentionally increased Aβ42 levels.

“Amyloid plaques don’t cause Alzheimer’s disease, but if the brain produces too much of it to defend itself against infections, toxins or biological changes, it can’t produce enough Aβ42, causing its levels to drop below a critical threshold,” Espay says. “That’s when symptoms of dementia appear.”

The team analyzed data from nearly 26,000 patients participating 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 Aβ42 levels after treatment were independently associated with slower cognitive impairment and clinical decline.

“Every story has two sides, even the one we’ve been telling ourselves about how anti-amyloid treatments work: They reduce amyloid,” Espay said.

“In fact, they also increase Aβ42 levels. Even if it’s not intentional, that’s why there may be a benefit. Our study shows that we can predict changes in cognitive outcomes in anti-amyloid trials at least as well by increasing Aβ42 as by decreasing amyloid.”

Espay said these findings fit well with his broader hypothesis about the root cause of Alzheimer’s disease, because increasing Aβ42 levels appears to improve cognition.

“If the problem with Alzheimer’s is loss of the normal protein, then increasing it should be beneficial, and this study showed that it is,” he said. “The story makes sense: Raising Aβ42 levels into the normal range is desirable.”

However, Espay says these results also represent a conundrum for clinicians, because removing amyloid from the brain is toxic and can cause the brain to shrink more quickly after antibody treatment.

“Should we give patients anti-protein therapy to increase their protein levels? I think the end, increasing Aβ42, does not justify the means, decreasing amyloid,” Espay said. Therapies that directly increase Aβ42 levels without targeting amyloid are at the heart of Espay and his group’s research.

Other co-authors of the study are Jesus Abanto of UC, Alok K. Dwivedi of Texas Tech University and Bruno P. Imbimbo of Chiesi Farmaceutici in Parma, Italy.