In 1906, the German doctor Alois Alzheimer was the first to describe the disease that bears his name. In 2022, a new scientific study now suggests hope for a treatment that makes it possible to stem this progressive cerebral deterioration, which results in the loss of memory and certain intellectual functions.
In 1906, psychiatrist and neuroanatomist Alois Alzheimer reported “a serious and peculiar pathological process in the cerebral cortex” at a meeting of psychiatrists in Tübingen, Germany. The case described was a 50-year-old woman who suffered from amnesia, delusions, hallucinations, aggression and confusion—conditions that all worsened until her untimely death, which occurred five years ago. During the autopsy, Alzheimer noted the presence of plaques in the patient’s brain. These plaques – aggregates of amyloid beta protein – are still thought to be responsible for Alzheimer’s disease today.
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However, this theory has two flaws. First, it does not explain why many people (some of whom are elderly) have plaque in the brain but do not suffer from neurological symptoms, such as memory loss. Second, clinical trials of drugs that reduce these plaques have been unsuccessful—except for one recent exception, which we’ll get to later.
When amyloid beta protein builds up as plaques (insoluble aggregates), the original soluble form of the protein, which performs important functions in the brain, is consumed and lost. Some studies have found that reducing the amount of soluble amyloid beta – called amyloid beta 42 – leads to worse clinical outcomes for patients.
In a recent study, published in Journal of Alzheimer’s Diseasewe tried to understand what was more related to the development of Alzheimer’s disease: the amount of plaques in the brain or the remaining amount of amyloid beta 42.
To answer this question, we examined data from a group of people who carry a rare inherited genetic mutation that puts them at high risk of developing Alzheimer’s disease. The participants were from the cohort study Dominantly inherited Alzheimer’s. We found that the decrease in amyloid beta 42 (the functional version of the protein) was more harmful than the presence of plaques (the insoluble aggregates of amyloid beta).
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The origins of dementia in Alzheimer’s
Participants were followed for an average of three years, and we found that those with high levels of amyloid beta 42 in their cerebrospinal fluid (CSF) (which surrounds the brain and spinal cord) were protected. Furthermore, their cognition did not deteriorate over the duration of the study. These results are consistent with many other studies that have shown the importance of amyloid beta 42 for memory and cognition.
They are also relevant because we studied people with the genetic mutation that increases the risk of developing Alzheimer’s disease, a group considered to offer the strongest evidence for the harmful nature of amyloid beta plaques. But even in this group, those with higher levels of amyloid beta 42 in their cerebrospinal fluid maintained normal cognitive functions, regardless of the amount of plaque in their brains.
It should also be mentioned that in some rare hereditary forms of Alzheimer’s disease – for example in carriers of the Osaka mutation or the Arctic mutation – people can develop dementia with low levels of amyloid beta 42, without the presence of plaques being detectable . This suggests that it was not the plaques that caused their dementia, but rather the lack of amyloid beta 42.
Lecanemab, the drug that is an exception
How will our results affect drug development and clinical trials for Alzheimer’s disease? Until the very recent trial of Lecanemab, an antibody that reduces plaque, all drug trials against Alzheimer’s disease had ended in failure.
Some medications have been designed to lower levels of amyloid beta 42, on the assumption that by lowering levels of the normal protein, patients will experience less plaque buildup. Unfortunately, these drugs often made patients worse.
Lecanemab was recently observed to have a small but significant effect in reducing cognitive decline. Previous studies have shown that this drug increases CSF amyloid beta 42 levels. This supports our hypothesis that increased normal amyloid protein may be beneficial.
We will know more after the results of the Lecanemab trials are published. At the moment we only have a press release from the manufacturers of the substance.
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A hope for treatment
We believe that future trials should focus on levels of amyloid beta 42 and whether it is beneficial to increase and restore its levels to normal values rather than seeking to eliminate it. This could be achieved by using proteins that are similar to amyloid beta 42 – called “analog proteins” – but are less likely to form aggregates than natural proteins.
This active protein replacement approach may become a promising new treatment avenue for Alzheimer’s disease and other diseases associated with protein aggregation, such as Parkinson’s disease and motor neuron diseases.
The original version of this article was published in The conversation.