Recent research tends to challenge the hypothesis favored for research into Alzheimer’s disease in recent decades. The causes of the disease can be different.
Have we been wrong about Alzheimer’s for decades? The main theory of how this disease works, known as the “amyloid cascade,” is increasingly being challenged in studies. This is despite the fact that it has served as the basis for most research over the past twenty years.
The exact causes and mechanisms of Alzheimer’s disease are still unclear, although it is the best known and most common form of dementia.
One of the scientific certainties about this pathology lies in the fact that the patients systematically present plaques of proteins called amyloid that form around the neurons and eventually destroy them.
The cascade hypothesis, which has been favored in recent decades, assumes that diseases arise from the formation of these plaques. But 30 years after the British biologist John Hardy formulated this theory, more and more scientists are wondering whether it is not a consequence of Alzheimer’s, but a primary cause.
Study defeats ongoing research
A study published this Thursday, June 2, in the journal Nature Neuroscience is the latest work to date questioning the primary role of amyloid plaques. It suggests that the disease process starts inside the neurons and not outside.
The researchers studied mice that had been genetically modified to induce an equivalent of Alzheimer’s. They found a dysfunction in the lysosomes, that small part of the neuron that allows it to “digest” useless or degraded components.
The research team found that when these lysosomes become damaged, they disrupt the neuron’s function. This mechanism then causes amyloid filaments to appear inside the cell long before plaques form outside. The latter could therefore be a consequence and not a cause, according to the hypothesis developed in this study.
A rebalancing of knowledge
This research alone obviously doesn’t make a decision, but it is part of a broader movement to challenge the theory of the amyloid cascade. This question is reinforced by the fact that there is no proven treatment for Alzheimer’s that aims to prevent the formation of amyloid plaques.
Only one drug, developed by the American company Biogen, has so far been approved by the American authorities in 2021. But its interest remains highly controversial within the scientific community.
However, some researchers are unwilling to flatly reject the hypothesis that has served as the basis of research over the past few decades, instead arguing for a rebalancing of knowledge. “There is still much evidence to support the value of the amyloid cascade hypothesis in explaining the pathogenesis of Alzheimer’s disease,” said British neurologist Tara Spire-Jones. But amyloid is far from explaining everything.
In late 2021, European researchers formulated a hypothesis at the intersection of the other two. It consists in considering that there are several forms of Alzheimer’s disease in which the amyloid cascade plays a more or less important role. After reviewing about 200 studies on this pathology, these scientists, led by the Italian Giovanni Frisoni, propose to divide Alzheimer’s disease into three main categories.
In this classification, while forms for which the amyloid cascade would be the main mechanism exist, they would affect a minority of patients. These are people who are often affected by an early form before the age of 50 and in whom the role of a specific genetic mutation seems to be proven.
The category that brings together the most patients, about half, is the third. It affects the forms of the disease where the role of amyloid plaques would be the least trigger.
By formulating the hypothesis of the existence of three Alzheimer’s diseases instead of just one, these researchers do not claim to invalidate the research carried out so far, but hope to refine the knowledge of this pathology. The goal is always the same: “Accelerate the development of strategies to prevent and treat the disease”.
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