Study: Decreased protein, not amyloid plaques, linked to Alzheimer's disease

Study: Decreased protein, not amyloid plaques, linked to Alzheimer’s disease

image: Alberto Espay, MD
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Credit: Photo/Colleen Kelley/UC Marketing + Brand

New research from the University of Cincinnati reinforces the hypothesis that Alzheimer’s disease is caused by a drop in levels of a specific protein, contrary to a prevailing theory that has been recently questioned.

UC researchers led by Alberto Espay, MD, and Andrea Sturchio, MD, in collaboration with the Karolinska Institute in Sweden, published the research Oct. 4 in the Journal of Alzheimer’s Disease.

Challenging the dominant assumption

The research is focusing on a protein called beta-amyloid. The protein normally performs its functions in the brain in a soluble form, that is, soluble in water, but it sometimes hardens into clumps, called amyloid plaques.

Conventional wisdom in the field of Alzheimer’s disease research for over 100 years has held that Alzheimer’s disease is caused by the buildup of amyloid plaques in the brain. But Espay and his colleagues speculated that the plaques are simply a consequence of declining levels of soluble amyloid beta in the brain. These levels decline because normal protein, in situations of biological, metabolic, or infectious stress, turns into abnormal amyloid plaques.

“The paradox is that so many of us accumulate plaques in our brains as we age, and yet so few of us with plaques develop dementia,” said Espay, professor of neurology at UC College. of Medicine, Director and Endowed President. from the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at UC Gardner Neuroscience Institute and a physician from UC Health. “Yet plaques remain at the center of our attention when it comes to biomarker development and therapeutic strategies.”

Sturchio noted that many research studies and clinical trials over the years have aimed to reduce amyloid plaques in the brain, and some have attenuated the plaques, but until the Sept. 27 announcement of a positive trial by Biogen and Eisai (lecanemab), neither slowed progression. of Alzheimer’s disease. More importantly, in support of their hypothesis, in some clinical trials that reduced levels of soluble amyloid beta, patients showed worsening clinical outcomes.

“I think this is probably the best evidence that reducing the level of the soluble form of the protein can be toxic,” said Sturchio, first author of the report and assistant research instructor at UC College of Medicine. “When finished, the patients got worse.”

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Previous search of the team found 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 the protein were more likely to have cognitive disorders.

In the current study, the team analyzed beta-amyloid levels in a subset of patients with mutations that predict overexpression of amyloid plaques in the brain, which would make them more likely to develop the disease. Alzheimers.

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

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

“What we have found is that individuals who are already accumulating plaques in their brains and who are able to generate high levels of soluble beta-amyloid have a lower risk of progressing to dementia over a period of three years,” Espay said.

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

“It only makes too much sense, if you’re detached from the biases 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 said. “Degeneracy is a process of loss, and what we lose turns out to be much more important.”

Next steps

Sturchio said research is progressing to study whether increasing levels of soluble amyloid beta in the brain is a beneficial therapy for patients with Alzheimer’s disease.

Espay said it will be important to ensure that the high levels of protein introduced into the brain do not later turn into amyloid plaques, as the soluble version of the protein is needed for normal functioning to impact the brain. .

On a larger scale, the researchers said they believe a similar hypothesis about the causes of neurodegeneration could be applied to other diseases, including Parkinson’s disease and Creutzfeldt-Jakob disease, with research also being underway in these areas.

For example, in Parkinson’s disease, a normal soluble protein in the brain called alpha-synuclein can harden into a deposit called Lewy bodies. The researchers hypothesize that Parkinson’s disease is not caused by the aggregation of Lewy bodies in the brain, but rather by a decrease in levels of normal soluble alpha-synuclein.

“We advocate that what may be more meaningful in all degenerative diseases is the loss of normal protein rather than the measurable fraction of abnormal protein,” Espay said. “The net effect is protein loss, not gain, as the brain continues to shrink as these diseases progress.”

Espay said he envisions a future with two approaches to treating neurodegenerative diseases: rescue medicine and precision medicine.

Rescue medicine resembles current work, studying whether increasing levels of key proteins like beta-amyloid leads to better outcomes.

“Interestingly, lecanemab, the recently reported beneficial anti-amyloid drug, does something that most other anti-amyloid treatments don’t besides reduce amyloid: it increases levels of beta- soluble amyloid,” Espay said.

Alternatively, precision medicine involves furthering the understanding of what is causing the levels of soluble amyloid beta to decline, whether it is a virus, toxin, nanoparticle, or biological or genetic process. If the root cause is treated, protein levels would not need to be increased as there would be no transformation of normal soluble proteins into amyloid plaques.

Espay said precision medicine would take into account that no two patients are the same, offering more personalized treatments. Researchers advance precision medicine through Cincinnati Cohort Biomarker Programa project to divide neurodegenerative diseases into biological subtypes in order to tailor biomarker-based therapies to those most likely to benefit.

“The Cincinnati Cohort Biomarker Program is dedicated to working to deploy the first success in precision medicine of this decade,” Espay said. “By recognizing the biological, infectious and toxic subtypes of Parkinson’s disease and Alzheimer’s disease, we will have specific treatments capable of slowing the progression of those affected.


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