What causes Alzheimer's? Groundbreaking study reveals it may be something unexpected

An investigation by Science Magazine reveals that one of the most influential research works on Alzheimer’s disease — the amyloid hypothesis, could be wrong. The research paper in question here was originally published in 2006, and it has been cited in over 2000 articles to this date. The study proposed that the formation of amyloid plaques in the human brain is the main cause of senile dementia.

Amyloid plaques are clumps of sticky and insoluble strands of a protein called amyloid-beta (amyloid-β) that sometimes occupy the free space between neurons and negatively impact brain activity. A new study conducted by a team of researchers at the University of Cincinnati (UC) and Karolinska Institute suggests that amyloid plaques are actually not a cause but a consequence of Alzheimer’s. Whereas the onset of the disease is actually linked to reduced levels of soluble beta-amyloid protein in the human body.

Not plaque but a protein is the key

The researchers of the new study examined the concentration of amyloid plaques and the amyloid-beta protein in two groups. The first group included people that had very high chances of suffering from Alzheimer’s according to the 2006 study. The researcher spotted mutations in their bodies which indicated the development of amyloid plaques in the future.

The second group involved healthy individuals. In both cases, the researchers noticed that individuals with low concentrations of soluble amyloid-beta protein were at greater risk of suffering from dementia. Whereas others that were more likely to have amyloid plaques in their brains in the future but had high concentrations of the protein witnessed normal brain activity.

Professor of Clinical Division Director at UC College of Medicine and one of the authors of the study, Alberto J. Espay said, “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.”

The concentration of soluble amyloid-beta protein decreases when it turns into insoluble amyloid plaques due to various stress factor that affects its metabolism. The researchers point out that many clinical trials in the past that focused on treating Alzheimer’s, attempted to eliminate amyloid plaques in the human brain. However, none of those approaches except one have proved to be effective against the disease.

Interestingly, even the one trial that has been successful in providing relief against Alzheimer’s also uses a drug (lecanemab) that not only eliminates amyloid plaques but also increases the concentration of soluble amyloid-beta protein. Moreover, according to the researchers, the trials during which the level of amyloid-beta protein went down ended with negative results.

First author and neurologist at Karolinska Institute, Andrea Sturchio wrote, “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.”

The research is not just limited to Alzheimer’s disease

Sturchio and his team believe that if their hypothesis about Alzheimer’s turned out to be true then the same theory could also be considered for finding the root cause of various other degenerative brain disorders such as the Creutzfeldt-Jakob disease, Parkinson’s disease, etc. For instance, many studies suggest that Parkinson’s is caused due to accumulation of insoluble Lewy bodies in the brain.

The researchers point out that it is possible the disease is actually resulting from low levels of soluble alpha-synuclein protein since Lewy bodies are also formed when the protein hardens and becomes insoluble. According to professor Espay, if we focus more on increasing the level of the soluble protein in the brain via medicines, instead of eliminating the insoluble deposits, there is a chance we might be able to treat brain degenerative disorders more effectively.

The researchers of the current study are now further aiming to find out if Alzheimer’s disease could be treated by increasing the concentration of soluble amyloid-beta protein in the human brain.

The study is published in the Journal of Alzheimer's Disease.