Health

Shocking Study Finds Decreased Proteins – Not Amyloid Plaques – Cause Alzheimer’s Disease

Alzheimer's Brain Disease

The prevailing theory is that Alzheimer’s disease is caused by the buildup of amyloid plaques in the brain. However, new research finds that it is actually caused by a decline in levels of a specific protein.

New research on patients with mutations published in the Journal of Alzheimer’s Disease.

Contrary to a prevailing theory that has been recently called into question, new research from the University of Cincinnati (UC) bolsters a hypothesis that Alzheimer’s disease is caused by a decline in levels of a specific protein.

UC researchers led by Alberto Espay, MD, and Andrea Sturchio, MD, in collaboration with the Karolinska Institute in Sweden, published the research on October 4, 2022, in the Journal of Alzheimer’s Disease.

Questioning the dominant hypothesis

This research study was focused on a protein called amyloid-beta. The protein normally carries out its functions in the brain in a form that is soluble, meaning that it is dissolvable in water. However, it sometimes hardens into clumps, known as amyloid plaques.

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

For more than 100 years, the conventional wisdom in the field of Alzheimer’s research stated that Alzheimer’s was caused by the buildup of amyloid plaques in the brain. However, Espay and his colleagues hypothesized that plaques are actually just a consequence of the levels of soluble amyloid-beta in the brain decreasing. These levels decrease because the normal protein, under situations of biological, metabolic, or infectious stress, transforms into the abnormal amyloid plaques.

“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,” said Espay. He is a a UC Health physician, a 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. “Yet the plaques remain the center of our attention as it relates to biomarker development and therapeutic strategies.”

Alberto Espay, MD, MSc, 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. Credit: Colleen Kelley/UC Brand + Creative

Sturchio noted that over the years many clinical trials and research studies have aimed at reducing amyloid plaques in the brain. Some have succeeded in lessening plaques, but until the September 27 announcement of a positive trial by Biogen and Eisai (lecanemab), none actually slowed the progression of Alzheimer’s disease. More importantly, in support of their hypothesis, in some of the clinical trials that reduced the levels of soluble amyloid-beta, patients showed worsening in clinical outcomes.

“I think this is probably the best proof that reducing the level of the soluble form of the protein can be toxic,” said Sturchio. He is the first author of the report and an adjunct research instructor at UC’s College of Medicine. “When done, patients have gotten worse.”

Research results

Previous research from the team found that regardless of the buildup of plaques in the brain, people with high levels of soluble amyloid-beta were cognitively normal, but those with low levels of the protein were more likely to have cognitive impairment.

Andrea Sturchio, MD. Credit: Provided

In the current study, the research team examined the levels of amyloid-beta in a subset of patients with mutations that predict an overexpression of amyloid plaques in the brain, which is thought to make them more likely to develop Alzheimer’s disease.

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

Even in this group of patients thought to have the highest risk of Alzheimer’s disease, the scientists observed similar results as 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,” Espay said.

The research found that people can remain cognitively normal regardless of the amount of amyloid plaques in their brains as long as they maintain a baseline level of soluble amyloid-beta in the brain above 270 picograms per milliliter.

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

Next steps

According to Sturchio, the research is moving forward to investigate whether increasing the levels of soluble amyloid-beta in the brain is a beneficial therapy for patients with Alzheimer’s.

Espay said it will be essential to ensure that the elevated levels of the protein introduced into the brain do not then turn into amyloid plaques, since the soluble version of the protein is needed for normal function to make an impact in the brain.

On a larger scale, the research team believes a similar hypothesis of what causes neurodegeneration can be applied to other diseases including Parkinson’s and Creutzfeldt-Jakob disease. Research is ongoing in these areas as well.

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

“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 said. “The net effect is a loss not a gain of proteins 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 looks like the current work, examining whether boosting levels of key proteins like amyloid-beta leads to better outcomes.

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

Alternatively, precision medicine entails going deeper to understand what is causing levels of soluble amyloid-beta to decrease in the first place, whether it is a virus, toxin, nanoparticle, or biological or genetic process. If the root cause is addressed, the levels of the protein wouldn’t need to be boosted because there would be no transformation from soluble, normal proteins to amyloid plaques.

Espay said precision medicine would provide more personalized treatments by taking into account the fact that no two patients are exactly alike. The researchers are making progress in precision medicine through the Cincinnati Cohort Biomarker Program, a project aiming to divide neurodegenerative diseases by biological subtypes in order to match therapies based on biomarkers to those most likely to benefit from them.

“The Cincinnati Cohort Biomarker Program is dedicated to working toward deploying the first success in precision medicine in this decade,” Espay said. “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.”

Reference: “High Soluble Amyloid-ß42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations” by Andrea Sturchio, Alok K. Dwivedi, Tarja Malm, Matthew J.A. Wood, Roberto Cilia, Jennifer S. Sharma, Emily J. Hill, Lon S. Schneider,Neill R. Graff-Radford, Hiroshi Mori, Georg Nübling, Samir El Andaloussi, Per Svenningsson, Kariem Ezzat, Alberto J. Espay and the Dominantly Inherited Alzheimer Consortia (DIAN), 16 September 2022, Journal of Alzheimer’s Disease.
DOI: 10.3233/JAD-220808

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  • What would be helpful to know is whether there are any natural ways to increase soluble amyloid proteins given it could easily be DECADES before anything is available as a treatment. People in danger of dementia NOW cannot wait that long.

    It's a bit like Covid-19 vaccines taking so long to be approved that the version they're treating is long gone by the time it's out and a new version has replaced it and so on and so on. Speed is of the essence, but traditional methodologies in medicine are so slow they lead to unnecessary suffering and death in the short term. They should at least offer potential treatments as an option to those facing dire conditions including terminal without any treatment. Some small chance of something helping may be better than zero.

    • You are making the assumption that this theory is valid. There just is no shortcutting. We don't know if that will work or not. There are things that can be done. Regular exercise, or sauna where heart rate is increased for a time, appears to reduce the progression of Alzheimer's. Getting regular and quality sleep is also very important. Smoking and alcohol are obviously bad. Things get more speculative from there. But whatever you try, you want there to be very low probability of making things worse.
      You can't just go with logic. We had logic for thousands of years, and it did little. It was only with experimentation and the genuine use of scientific method that we really kicked progress into high gear. Logic may suggest a course of action, but it is still just a guess until the science is done. More amyloid could be just as bad or worse than less.

    • Try taking an Amono acid supplement. All protein is built by your body from amino acids in your diet. Protein eaten is broken down by digestion. There are eight amino acids that the human body cannot make. Also one can have absorption issues. So there are a number of perfect amino acid mix products online and in health food stores. For $1 a day it might not hurt to try. Years ago I noticed if I got a rare headache it could be relieved by eating some protein an egg or nuts or meat or fish.

  • Yet another theory, but we need new theories, because the standard idea has been failing for decades. Other compelling new theories suggest an immune system component.
    And the idea that the plaques themselves pose no issue is not completely rational in my opinion. Any obstruction, or inundation of neurons, is likely to reduce mental performance. Though, it is unclear how much function is lost in this way.
    It is also concerning that increasing amyloid beta could, in the presence of amyloid plaques, rapidly convert into more and larger plaques. I do hope they do quite a little concept validation in animal models and tissue samples.
    I think we also have to look for chaperone molecules that support the correct molecular conformation of amyloid beta. If we can boost these levels, perhaps we can prevent plaque formation or halt accumulations.
    And amyloid plaque accumulations are a natural reaction to infection in the brain, we must do more to immunize people from these pathogens. We need vaccines and cures for all the herpes viruses, especially. That whole group of pathogens stays latently in the body almost certainly causing issues, same with many adenoviruses, and some others. And toxoplasmosis I don't think is benign either. And it can't hurt to limit heavy metal toxins, such as mercury, lead, cadmium and arsenic in our food. We have also given a pass to many chemicals produced before the emergence of regulatory agencies. We need to go back and evaluate these things and ban the use of dangerous toxins...especially anything that enters the air water or crops.
    We can also investigate the other direction. We can track where people lived, what they ate, what toxins are in their bodies and bones, what infections they have had. With big data, we might be able to pick out the potential causes, protective nutrients, or behaviors, and investigate all these further.

    And the things we have seen that appear to be beneficial, we need to encourage and investigate further: exercise, sauna, good nutrition, clean air (more homes with HEPA air filtration might be of benefit), quitting smoking, quitting drinking, quality regular sleep and treating sleep apnea.

    And there are a number of interesting promising ideas with less evidence that deserve far more testing, like limiting "Advanced Glycation End-products" in the diet, and combating the formation of these cross-links in the body. Hyperbaric oxygen treatment looks very interesting. And plasma replacement therapy also looks very interesting. Recent experiments, that appear to restore the thalamus, are interesting as well.

    • I would add the use of near infrared light stimulation to the brain using pulsed 1070nm light. This was shown in clinical trials with dementia and normal subjects to significantly improve cogntion, motor function and executive functions. The Neuradiant 1070 4Q from Neuronic Devices Ltd. is one example of devices currently in use with positive results. more at quietmindfdn.org

  • Not sure what the other commenters where looking for in this article. This site post the results of students seeking to publish. Of course they are rough and non professional. These works are not meant to change the paradigm, just get the kids a PhD. Go to Scientific America if you want to argue. just sayin'.....

  • Due to PASC, any number of seniors are self-mesicating with Nattokinase, Serrapeptase to dissolve microclotting (hopeful, that this might help "dissolve Tau Protein bundles.") Is this likely to cause issues, as this becomes more prevalent?

  • Sometimes a particular protein deficiency can be caused by an specific essential amino deficiency. Through a diatary or absorption deficiency. Thus it would not hurt if people took an amino acid supplement that supplied the eight essential amino acids in a very easily absorbed form in the correct ratio. There are a number of different available perfect amino mix products on the market online or at most health food stores. For $30 a month it might be worth a try.

    • Actually, we get protein too regularly. This would never happen in nature. There would be times where we had to settle for berries, or grass, maybe for a week or more at a time. We were designed to fast occasionally.
      When we get very little protein, our bodies reduce IGF-1 and things change gears. Our bodies start scavenging protein from less important cells. Sounds bad, but it isn't. It kills senescent cells that are spewing toxins and kills other old, decrepit cells. When we resume protein intake, there is a time of renewal, and we get fresh new cells, and one is generally healthier after than before.
      Thing is, this is probably not a great approach for the elderly. This is more of something to do when generally healthy to prevent future health issues.
      Fasting also stimulates the brain. Your body assumes you need a mental boost because your hunts are coming up dry.
      A true fast would probably be rare, but near fasts with low protein probably happened several times a year.

  • Time for new paradigms. The old ones only benefit those wanting financial gains by medication not the true medicine, food!

By
University of Cincinnati

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