Alzheimer’s: the main theory on the origin of the disease called into question

Recent research tends to question the hypothesis favored in recent decades to conduct research on Alzheimer’s. The root causes of the disease could be different.

Have we been wrong about Alzheimer’s for decades? The main theory concerning the operation of this disease, known as “amyloid cascade”, is increasingly questioned in studies. This, even though it has served as the basis for most research for the past twenty years.

At present, the precise causes and mechanisms of Alzheimer’s disease still remain mysterious, although it is the best known and most frequent dementia.

One of the certainties of science about this pathology lies in the fact that the patients systematically present plaques of proteins, called amyloid, which form around the neurons and eventually destroy them.

The cascade hypothesis, favored in recent decades, assumes that disease arises from the formation of these plaques. But, thirty years after the formulation of this theory by the British biologist John Hardy, more and more scientists are wondering if it is not a consequence of Alzheimer’s among others, rather than of 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 to question the primary role of amyloid plaques. It suggests that the disease process starts inside the neurons and not outside.

The researchers studied mice genetically modified to induce an equivalent of Alzheimer’s. They noted a dysfunction of the lysosomes, this small part of the neuron which allows it to “digest” useless or degraded components.

The research team has established that by being damaged, these lysosomes disrupt the functioning of the neuron. This mechanism then causes the appearance of amyloid filaments in the cell, long before the formation of plaques on the 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 does not make it possible to decide, but it is part of a more general movement to question the theory of the amyloid cascade. This questioning is reinforced by the fact that no treatment against Alzheimer’s has yet proven itself by aiming to prevent the formation of amyloid plaques.

Only one drug, developed by the American Biogen, has so far been approved by the American authorities, in 2021. But its interest remains highly contested within the scientific community.

Some researchers, however, are not ready to reject outright the hypothesis that has served as the basis for research in recent decades, pleading instead for a rebalancing of knowledge. “There is still a lot of evidence for 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.

At the end of 2021, European researchers formulated a hypothesis at the crossroads of the other two. It consists of considering that there are several forms of Alzheimer’s disease, in which the amyloid cascade plays a more or less important role. After reviewing some 200 studies on this pathology, these scientists, led by the Italian Giovanni Frisoni, suggest dividing Alzheimer’s disease into three main categories.

In this classification, the forms for which the amyloid cascade would be the main mechanism do exist, but would concern a minority of patients. These are people often affected by an early form, before the age of 50, and in whom the role of a specific genetic mutation seems proven.

The category that brings together the largest number of patients, about half, is the third. It concerns the forms of the disease in which the role of amyloid plaques would be the least trigger.

The longer we are exposed to our phones, the earlier the disease would appear and with more severe symptoms.

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 objective is always the same: “accelerate the development of strategies to prevent and treat the disease”.

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