Contrary to a long-held belief that has lately been challenged, a new study from the University of Cincinnati supports the idea that Alzheimer’s disease is caused by a drop in levels of a particular protein.

The study was published today in the Journal of Alzheimer’s Disease by UC researchers led by Alberto Espay, MD, and Andrea Sturchio, MD, in partnership with the Karolinska Institute in Sweden.

Questioning the most common theory

The research focuses on the amyloid-beta protein. The protein typically acts in the brain as a soluble form that can be dissolved in water, but it can occasionally harden into plaques called amyloid plaques.

For more than a century, it was accepted wisdom in the area of Alzheimer’s research that amyloid plaque formation in the brain was the primary cause of the disease. Espay and his associates, however, proposed that plaques are merely a byproduct of the decline in soluble amyloid-beta levels in the brain. These levels fall because normal proteins turn into aberrant amyloid plaques in the presence of biological, metabolic, or viral 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,” explains professor Espay. “Yet the plaques remain the center of our attention as it relates to biomarker development and therapeutic strategies.”

Sturchio remarked that numerous research studies and clinical trials have been conducted over the years to reduce amyloid plaques in the brain, and some have been successful. However, prior to the September 27 announcement of a successful trial by Biogen and Eisai (lecanemab), none had slowed the progression of Alzheimer’s disease. More crucially, patients’ clinical results deteriorated in certain clinical studies that reduced the levels of soluble amyloid-beta, supporting their hypothesis.

“I think this is probably the best proof that reducing the level of the soluble form of the protein can be toxic,” adds first author Sturchio. “When done, patients have gotten worse.”

Results of the study

In previous research, the team found that people with high levels of soluble amyloid-beta were able to think and reason normally, even if they had a lot of plaques in their brains. People with low levels of the protein were more likely to have cognitive impairment.

The team examined the levels of amyloid-beta in a subset of individuals in the current study who had mutations that were thought to increase their risk of developing Alzheimer’s disease and predicted an overabundance of amyloid plaques in the brain.

These mutations were “one of the strongest supports to the hypothesis of amyloid toxicity,” according to Sturchio. “We studied that population because it offers the most important data.”

Even though this group of patients was thought to have the highest risk of Alzheimer’s disease, the researchers found similar results to the study of the general population.

“What we found was 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,” adds Espay.

According to the study, people with soluble amyloid-beta levels in the brain that are above 270 picograms per milliliter can maintain cognitive function regardless of the presence of amyloid plaques in their brains.

“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 says. “Degeneration is a process of loss, and what we lose turns out to be much more important.”

Next actions

According to Sturchio, studies are being conducted to see whether giving Alzheimer’s patients more soluble amyloid-beta in the brain is an effective treatment.

Since the soluble form of the protein is required for normal function to have an effect in the brain, Espay said it will be crucial to prevent the elevated quantities of the protein from being introduced into the brain from turning into amyloid plaques.

In a broader sense, the researchers asserted that they think a similar theory of what causes neurodegeneration can be applied to other illnesses including Parkinson’s and Creutzfeldt-Jakob disease, where research is also ongoing.

In Parkinson’s disease, for instance, a normally soluble protein in the brain called alpha-synuclein can transform into a Lewy body deposit. According to the researchers, a drop in the concentration of healthy, soluble alpha-synuclein rather than the accumulation of Lewy bodies in the brain is what causes Parkinson’s disease.

“We’re advocating that what may be more meaningful across all degenerative diseases is the loss of normal proteins rather than the measurable fraction of abnormal proteins,” Espay adds. “The net effect is a loss not a gain of proteins as the brain continues to shrink as these diseases progress.”

Espay stated that he sees rescue medicine and precision medicine as two future modes of treatment for neurodegenerative illnesses.

Currently, researchers are examining whether increasing quantities of important proteins such as amyloid-beta results in better outcomes.

Intriguingly, lecanemab, a recently discovered good anti-amyloid medication, also raises levels of soluble amyloid-beta, which is something that most other anti-amyloid medications don’t do, according to Espay.

As an alternative, precision medicine requires digging deeper to determine what, if any virus, toxin, nanoparticle, biochemical, or genetic process, is causing levels of soluble amyloid-beta to fall in the first place. If the underlying reason is resolved, increasing protein levels wouldn’t be necessary because there wouldn’t be any conversion of soluble, healthy proteins into amyloid plaques.

According to Espay, precision medicine would recognize that no two people need the same therapy. The Cincinnati Cohort Biomarker Program, a project that aims to categorize neurodegenerative illnesses by biological subgroups in order to match medicines based on biomarkers to those most likely to benefit from them, is helping researchers advance precision medicine.

“The Cincinnati Cohort Biomarker Program is dedicated to working toward deploying the first success in precision medicine in this decade,” Espay adds. “By recognizing biological, infectious and toxic subtypes of Parkinson’s and Alzheimer’s, we will have specific treatments that can slow the progression of those affected.”

Source: 10.3233/JAD-220808

Image Credit: Getty

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