Alzheimer’s: the main theory on the origin of the disease called into question 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 assumption about how the disease works is increasingly being questioned, which could upset the path to a drug. Qualified as the “amyloid cascade”, this hypothesis has served as the basis for most research against the disease for the past twenty years, with almost non-existent success for the time being.

Because Alzheimer’s disease may be the most well-known and most frequent dementia, its precise causes and mechanisms are largely unknown. Among the certainties, we know that patients systematically present plaques of proteins, called amyloid, which form around their neurons and eventually destroy them. But is it a primary cause or the consequence of other phenomena? The “cascade” hypothesis makes the first bet: all disease stems from the formation of these plaques.

The disease could start inside neurons

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

Carried out on genetically modified mice to induce an equivalent of Alzheimer’s disease, this study highlights a dysfunction of the lysosomes, this small part of the neuron which is used to “digest” useless or degraded components. 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. The authors therefore hypothesize that these are a consequence and not a cause.

“These new elements upset what we think about the progression of Alzheimer’s disease,” summarized in a press release the American biologist Ralph Nixon, who supervised this study within the University of New York. In reality, this work alone does not change the situation, in particular because it will be necessary to confirm that the same mechanisms are at work in humans. But this study is part of a more general movement to question the theory of the amyloid cascade for several years.

Still evidence in favor of the amyloid cascade

Behind this skepticism, there is an observation. While this theory has guided almost all of the pharmaceutical industry’s efforts against the disease, no treatment has been proven to prevent the formation of amyloid plaques. 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.

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Should we reject this hypothesis altogether? No, say some researchers, who rather refer to a rebalancing of knowledge. “There is still a lot of evidence for 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 explaining everything. »

One of the ways of reconciling 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 at the end of 2021 by European researchers, who reviewed some 200 studies on Alzheimer’s disease, then published their conclusions in the journal Nature Reviews Neuroscience.

Three Alzheimer’s diseases instead of one?

These researchers, led by the Italian Giovanni Frisoni, suggest dividing Alzheimer’s disease into three main categories. In the first, the amyloid cascade would be the main mechanism. But 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, in which the role of amyloid plaques would be the least trigger, would concern by far the largest number of patients: around half. Three Alzheimer’s diseases instead of one? This new perspective could “accelerate the development of strategies to prevent and treat Alzheimer’s disease”, conclude the researchers.

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