Where does Alzheimer’s disease come from? Study challenges main theory

ALZHEIMER – “These new elements upset what we think about the progression of Alzheimer’s disease”, concluded the American biologist Ralph Nixon, following the publication of a study on Alzheimer’s disease, which he directed, in the review Nature Neuroscience.

Published Thursday, June 2, it describes new mechanisms that can lead to Alzheimer’s disease and thus adds to the movement to question the main hypothesis on the functioning of the disease. It is indeed the hypothesis of the “amyloid cascade” which has served as the basis for most research for the past twenty years, but without apparent success.

Although Alzheimer’s disease is the most common dementia, its causes and precise mechanisms remain largely unknown. Among the certainties: that patients systematically present plaques of proteins, called amyloid, which form around their neurons and end up destroying them.

But is it a primary cause or the consequence of other phenomena? According to the “cascade” hypothesis, all disease stems from the formation of these plaques. What is less and less consensus among scientists.

Latest work to date to question this hypothesis: the study published Thursday, June 2 in the journal Nature Neuroscience. According to this, the disease process would indeed start inside the neurons and not outside. Carried out on genetically modified mice to induce an equivalent of Alzheimer’s disease, it highlights a dysfunction of the lysosomes, this small part of the neuron is used to “digest” useless or degraded components.

Extensive questioning of the amyloid cascade theory

The researchers have established that these lysosomes are damaged and disrupt the functioning of the neuron. Above all, this mechanism causes the appearance of amyloid filaments in the cell, long before the appearance of plaques on the outside. Amyloid plaques would therefore be a consequence and not a cause of the disease.

Although these works do not, however, on their own change the situation, in particular because it will be necessary to confirm that the same mechanisms are at work in humans, they are part of a more general movement to question the theory of amyloid cascade.

No treatment aimed at preventing the formation of amyloid plaques has indeed been proven against the disease. Only a drug developed by the American Biogen was approved, in 2021, by the American authorities, but its interest remains highly contested within the scientific community.

“There is still a lot of evidence of the interest of the amyloid cascade hypothesis in explaining the pathogenesis of Alzheimer’s disease”, nevertheless nuances the British neurologist Tara Spire-Jones with AFP, not rejecting this first hypothesis. “But amyloid is far from explaining everything,” she points out.

Three Alzheimer’s diseases?

Several researchers suggest instead a rebalancing of knowledge, considering that there are several forms of Alzheimer’s disease, in which the amyloid cascade plays a more or less important role.

At the end of 2021, several European researchers, led by the Italian Giovanni Frisoni, had suggested dividing Alzheimer’s diseases into three main categories, after reviewing some 200 studies on them.

If in the first, the amyloid cascade would be the main mechanism, this would represent a minority of patients, often suffering from an early form before the age of 50, and in whom the role of a specific genetic mutation seems proven. On the other hand, the last category of Alzheimer’s, in which the role of amyloid plaques would be the least trigger, would concern half of the patients, ie by far the greatest number of patients.

See also on The HuffPost: “This former ballerina has Alzheimer’s and hasn’t forgotten the ‘Swan Lake’ dance”

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