Alzheimer's disease is the most common form of dementia, for which researchers are still searching for a cure. As a starting point, the amyloid cascade hypothesis is used: an accumulation of the amyloid-beta protein would cause neurons to die. However, some studies contradict the hypothesis. Rejecting the amyloid hypothesis would have major consequences but sticking to an incorrect hypothesis can be even more harmful.
For more than 100 years, scientists have linked Alzheimer's to abnormal protein accumulations in the brain: amyloid plaques (clumps) and entanglements of the tau protein. These observations have led to the amyloid-cascade hypothesis, which says that these amyloid plaques cause Alzheimer's. The appeal of this hypothesis is its simplicity: if these plaques cause the disease, their presence can be used for early diagnosis and even treatment.
Testing the hypothesis
Should amyloid-beta indeed be the cause of Alzheimer's, this can be proven using two types of experiments. The first experiment would be to introduce amyloid plaques to healthy brains. According to the hypothesis, these brains should become diseased. The second experiment would be the opposite: to remove the plaques from Alzheimer's brains. According to the hypothesis, these brains should get better, or at least remain stable.
Can we make healthy brains sick?
The first experiment looked at both humans and mice. It has been shown that people can have substantial amounts of amyloid-beta in their brains and still show little to no symptoms of dementia. This would even be the case in 25-30% of all elderly with healthy cognitive abilities. As for the mice, we can be more definite: genetic manipulations that cause significant amounts of amyloid-beta rarely lead to the cognitive symptoms of Alzheimer's disease.
Conclusion: you cannot cause the disease by exposing healthy brains to the suspected culprit.
Can we make sick brains better?
There is also evidence for the second type of experiment from both humans and mice. However, the results are not unequivocal. In mouse models of Alzheimer's disease, the accumulation of amyloid plaques was successfully prevented and even removed. After this, the behavior of the mice improved, consistent with the hypothesis. An important note here is that the functioning of the mice returned to 100%. If this mouse model really approximated the disease this should be impossible, because the hallmark of Alzheimer's is that the damage is irreversible. So it is unclear how much value we can put on these results.
The human approach was less successful. As in mice, attempts were made to immunize humans against amyloid-beta. These studies had to be terminated early because of numerous side effects. On the bright side: patients who did not suffer the side effects responded well to the trial, developing antibodies against the protein. However, their cognitive symptoms did not improve.
Cautious conclusion: when you remove the protein plaques from the brain, people still have Alzheimer's.
What now? What do these results mean for the hypothesis that Alzheimer's is caused by harmful plaques? Taken together the studies described above do not imply that plaques do not play a role in Alzheimer's, but that they are probably not the only or direct cause. Therefore, it is time to put aside the hypothesis and look for alternative explanations for the disease. There are plenty of options already at hand: problems with autophagy and/or lysosomes, calcium homeostasis, inflammation of the nervous system, genes, oxidative damage, glucose metabolism... Only some of the factors that scientific research has already uncovered. We certainly don't have to sit still!
Edit 2022: Meanwhile, researchers have been working hard to figure out exactly where the problem lies. Recent research gives strong indications there are problems with lysosomes. This is thought to be causing the functioning of neurons to be impaired, resulting in the death of neurons. This death of neurons only then leads to the formation of plaques.
Author: This article is a previously published brainmatters article written by Mireille van Berkel (3-8-15) and edited by Loes Beckers in 2022.
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