In 1906, Alois Alzheimer, a psychiatrist and neuroanatomist, reported a case to a psychiatrist meeting in Tübingen, Germany, which he described as “a special severe disease process of the cerebral cortex.” The case was about a 50-year-old woman who suffered from memory loss, delusions, hallucinations, aggression and confusion, and all symptoms worsened until she died five years later.
At autopsy, Alzheimer’s noticed prominent plaques in his brain. These plaques, identified as clumps of amyloid-beta protein, are still considered the cause of Alzheimer’s disease.
However, there are two major problems with this theory. The first of these problems does not explain why many subjects (even the elderly) have plaques in their brains in the absence of any neurological symptoms such as memory loss. Second, clinical trials for drugs that reduce these plaques have failed (with one last exception).
When amyloid-beta proteins accumulate as plaques (insoluble clumps), the original soluble form of the protein that performs important functions in the brain is consumed and lost. Some studies show that low levels of soluble amyloid-beta, called amyloid-beta 42, cause patients to have worse clinical outcomes.
What causes Alzheimer’s?
Researchers from the Karolinska Institutet Clinical Neuroscience PhD Student Medical Doctor Andrea Sturchio, Laboratory Medicine Research Scientist Kariem Ezzat, and Professor of Laboratory Medicine Samir EL Andaloussi in a recent study published in the Journal of Alzheimer’s Disease, Alzheimer’s disease progression It was investigated whether the amount of plaque in the brain or the amount of remaining amyloid-beta 42 was more important for cancer.
To answer this question, we analyzed data on a group of people with a rare inherited gene mutation at high risk of developing Alzheimer’s disease. Participants were recruited from the Dominantly Inherited Alzheimer’s Network cohort study.
In this study, depletion of Amyloid-beta 42 (the functional version of amyloid-beta) was found to be more harmful than the amount of plaques (insoluble clumps of amyloid beta).
Participants were followed for an average of three years, and those with high levels of amyloid-beta 42 in their cerebrospinal fluid (fluid around the brain and spinal cord) were found to be preserved and their cognition preserved throughout the study period. These results were in agreement with many studies showing the important functions of amyloid-beta 42 in memory and cognition.
It’s also said that in some rare, inherited forms of Alzheimer’s disease, people with low amyloid-beta 42 levels and no detectable plaques can develop dementia, suggesting that the dementia is not caused by plaques, but low amyloid-beta 42 levels, the study states.
New hope for Alzheimer’s patients
These findings could have a significant impact on drug development and clinical trials for Alzheimer’s disease. As noted, all drug trials in Alzheimer’s disease have failed until the last trial with Lecanemab, an antibody drug that reduces plaques.
Some drugs were designed to reduce amyloid-beta 42 levels based on the rationale that patients would accumulate less plaque if normal protein levels were reduced, but these drugs often made the patient’s condition worse.
It was recently reported that Lecanemab has a small but significant effect in reducing cognitive decline. According to previous studies, this drug increases the levels of amyloid-beta 42 in CSF, which, once again, is in line with the hypothesis proposed in the study that the increase of normal amyloid protein may be beneficial.
In other words, focusing on amyloid-beta 42 levels in future trials and examining the effect of increasing these levels may offer a new avenue of treatment for Alzheimer’s disease and other protein deposition diseases.
Detailed results of the lecanemab trial will be announced in more detail in the near future.
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