Alzheimer’s: the main theory on the origin of the disease questioned by several studies

Earthquake in the medical world. After decades of study, what if anti-Alzheimer’s research was actually on the wrong track? The main hypothesis about the functioning of the disease is increasingly being questioned, which could go to work for a drug. Called the “amyloid cascade”, this hypothesis has been the basis of most research against the disease for about twenty years, with almost no success at the moment.

Because Alzheimer’s disease is the best known and most common dementia, its exact causes and mechanisms are largely unknown. Among the certainties, it is known that patients systematically have plaques of proteins, called amyloids, which form around their neurons and eventually destroy them. But is it a primary cause or a consequence of other phenomena? The “waterfall” hypothesis is the first bet: all the disease would result from the formation of these plaques.

The disease could start inside the neurons

Or, thirty years after its formulation by the British biologist John Hardy, this theory is becoming less and less popular among scientists. Latest work to date calls into question the primary role of amyloid plaques, a study published Thursday in the journal Nature Neuroscience suggests that the process of the disease starts inside neurons and not outside.

Carried out in genetically modified mice to induce an equivalent of Alzheimer’s disease, this study highlights a dysfunction of lysosomes, this small part of the neuron that was used to “digest” unnecessary or degraded components. Researchers have found that these lysosomes are damaged and disrupt the functioning of the neuron. Above all, what mechanism causes the appearance of amyloid filaments in cells, well before the appearance of plaques on the outside. The authors therefore hypothesize that the latter are a consequence and not a cause.

“These new elements are upsetting what is thought to be the progression of Alzheimer’s disease,” said a statement from American biologist Ralph Nixon, who oversaw the study at New York University. In reality, these works alone do not change the situation, especially since it will confirm that the same mechanisms are at work in humans. But this study has been part of a more general movement to challenge the theory of the amyloid cascade for several years.

Still evidence in favor of the amyloid cascade

Behind this skepticism is a finding. While this theory has guided almost every effort of the pharmaceutical industry against the disease, no treatment has been proven to prevent the formation of amyloid plaques. Only one drug developed by American Biogen has been approved by the US authorities in 2021, but its interest remains highly contested in the scientific community.

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Should this hypothesis be rejected en bloc? No, say some researchers, who are more concerned with rebalancing knowledge. “You still know more evidence of the interest of the amyloid cascade hypothesis in explaining the pathogenesis of Alzheimer’s disease,” said British neurologist Tara Spire-Jones. “But amyloid is far from all.” ยป

One way to reconcile these positions is to consider that there are several forms of Alzheimer’s disease, in which the amyloid cascade plays a more or less important role. This is the idea formulated in late 2021 by European researchers, who reviewed some 200 studies on Alzheimer’s disease and then published their findings in the journal Nature Reviews Neuroscience.

Three Alzheimer’s Diseases Instead of One?

These researchers, led by Italian Giovanni Frisoni, suggest dividing Alzheimer’s disease into three broad categories. In the first, the amyloid cascade would be the main mechanism. However, this represents a minority of patients, often affected by an early form before the age of 50, and in whom the role of a precise genetic mutation seems to be proven.

On the other hand, in the last category, in which the role of amyloid plaques would be the least declined, far the largest number of patients were concerned: about half. Three Alzheimer’s Diseases Instead of One? This new view could “accelerate the development of strategies for the prevention and treatment of Alzheimer’s disease”, conclude the researchers.

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