New data indicate that this protein, and not amyloid plaques, is the cause of the development of Alzheimer’s disease. New research from the University of Cincinnati ( ) supports the hypothesis that Alzheimer’s disease is caused by low levels of a specific protein, in contrast to the recently questioned prevailing theory linking it to amyloid plaques.

The researchers, led by Dr. Alberto Espai and Dr. Andrea Storchio, in collaboration with the Karolinska Institutet in Sweden, have published their work in the “Journal of Alzheimer’s Disease.” The research focuses on a protein called beta-amyloid, which normally performs its functions in the brain in a soluble form, that is, in water, but sometimes solidifies into clumps called amyloid plaques.

For more than 100 years, research in Alzheimer’s disease has confirmed that it is caused by the buildup of amyloid plaques in the brain. But Espi and colleagues speculate that the plaques are simply the result of low levels of soluble beta-amyloid in the brain. These levels decrease because the normal protein, under the influence of biological, metabolic or infectious stress, turns into abnormal amyloid plaques.

“The irony is that many of us develop plaques in our brains as we age, yet very few of us who have these develop dementia,” says Espay, MD, professor of neurology at the University College of Medicine. UC, director and chief of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute and a physician at UC Health.

“However, plaques remain at the center of our attention in terms of developing biomarkers and therapeutic strategies,” he adds.

Sturchio points out that over the years there have been many research and clinical trials aimed at reducing amyloid plaques in the brain, some of which have reduced the plaques, but until last Tuesday’s announcement of a positive trial by Biogen and Eisai (lecanemab), neither had slowed. Alzheimer’s disease progression. More importantly, to support their hypothesis, in some clinical trials that reduced levels of soluble beta-amyloid, patients experienced deteriorating clinical outcomes.

“I think this is probably the best evidence that reducing the level of the soluble form of the protein can be toxic,” says Storchio, first author of the report and an associate research fellow at the university’s School of Medicine. University of California. When this was done, the patients’ condition worsened.

Previous research by the team showed that regardless of plaque buildup in the brain, people with high levels of soluble beta-amyloid were cognitively normal, while those with low levels of this protein were more likely to have cognitive impairment.

In the current study, the team analyzed beta-amyloid levels in a subset of patients with mutations that predict increased expression of amyloid plaques in the brain, making them more likely to develop the disease. Alzheimer’s.

“One of the strongest arguments for the amyloid toxicity hypothesis was based on these mutations,” said Storchio. “We studied this population because it provides the most important data.”

Even in this group of patients considered to be at highest risk of developing Alzheimer’s disease, the researchers obtained results similar to those of the general population study.

“What we found is that people who already form plaques in their brains and are able to produce high levels of soluble beta-amyloid have a lower risk of progressing to dementia over a three-year period,” notes Mr. Espy.

Research has found that with a baseline level of soluble beta-amyloid in the brain above 270 pg per milliliter, people can remain cognitively normal regardless of the amount of amyloid plaques in their brain.

“It makes perfect sense, if we let go of the prejudices we’ve created for too long, that the neurodegeneration process is caused by something we lose, which is beta-amyloid, not something we gain. Amyloid plaques,” says Espai. Decay is a process of loss, and what we lose turns out to be much greater.

Storchio notes that research is progressing to examine whether increasing levels of soluble beta-amyloid in the brain may be a beneficial treatment for Alzheimer’s patients.

For his part, Mr. Espy cautions that it will be important to ensure that high levels of the protein being introduced into the brain do not later turn into amyloid plaques, because the soluble version of the protein is necessary for normal functioning to have an effect in the brain.

More broadly, researchers believe that a similar hypothesis about the causes of neurodegeneration could apply to other diseases, including Parkinson’s disease and Creutzfeldt-Jakob disease, as research continues in these areas. also.

For example, in Parkinson’s disease, a natural soluble protein in the brain called alpha-synuclein can solidify into deposits called Lewy bodies. Researchers hypothesize that Parkinson’s disease is not caused by a buildup of Lewy bodies in the brain, but by low levels of natural and soluble alpha-synuclein.

“We argue that in all degenerative diseases, what is more important is the loss of the normal protein rather than the measurable portion of the abnormal protein,” Espy says. The end effect is protein loss, not protein gain, with the brain continuing to shrink as these diseases progress.

Mr. Espai envisions a future with two approaches to treating neurodegenerative diseases: rescue medicine and precision medicine. Rescue Medicine is similar to current work, which is looking at whether increasing levels of key proteins such as beta-amyloid leads to better outcomes.

“Interestingly, lekanimab, the anti-amyloid drug that has recently been reported to be beneficial, does something that most other anti-amyloid therapies do not do besides reducing amyloid: it increases levels of soluble amyloid beta,” Espai notes.

Precision medicine, on the other hand, involves trying to understand the reasons for low levels of soluble beta-amyloid, whether it is a virus, toxin, nanoparticle, biological or genetic process. If the root cause is addressed, there is no need to increase protein levels because the conversion of normal soluble proteins into amyloid plaques does not occur.

Espai notes that precision medicine will take into account that no two patients are the same, allowing for more personalized treatments. Researchers are working to advance precision medicine through the Cincinnati Biomarker Cohort Program, a project that aims to segment neurodegenerative diseases by biological subtypes to match biomarker-based therapies with those they are most likely to develop. benefit.

“The Cincinnati Biomarker Cohort Program is dedicated to working to deploy the first precision medicinal product of this decade,” says Espy. By learning about the biological, infectious, and toxic subtypes of Parkinson’s and Alzheimer’s disease, we will have targeted therapies able to slow the progression of sufferers.