Alzheimer’s disease: the main theory about the origin of the disease is called into question by many studies

Earthquake in the world of medicine. After decades of study, what if anti-Alzheimer’s disease research is actually going down the wrong track? The main assumption about how the disease works is increasingly being questioned, which could upset the path to medicine. Classified as the “amyloid cascade,” this hypothesis has served as the basis for most research against the disease over the past 20 years, with virtually no success at present.

Since Alzheimer’s disease may be the best-known and most common dementia, its exact causes and mechanisms are largely unknown. Among the established facts, we know that patients systemically present with plaques of proteins, called amyloid, which form around their neurons and eventually destroy them. But is it a major cause or the result of other phenomena? The “waterfall” hypothesis presents the first bet: all diseases result from the formation of these plaques.

The disease can start within the nerve cells

However, thirty years after it was formulated by British biologist John Hardy, this theory is less unanimous among scientists. The latest work to date to question the essential role of amyloid plaques, a study published Thursday in the journal Nature Neuroscience suggests that the disease process begins inside, not outside, neurons.

This study was conducted in mice genetically engineered to cause the equivalent of Alzheimer’s disease, and highlights a dysfunction of lysosomes, the tiny part of neurons that is used to “digest” useless or degraded components. Researchers have proven that these particles damage and disrupt the functioning of neurons. Above all, this mechanism causes amyloid filaments to appear in the cell, long before plaques appear outside. The authors therefore assume that this is a consequence, not a cause.

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

There is still evidence in favor of amyloid streak

Behind this doubt, there is a note. While this theory has guided nearly all of the drug industry’s efforts against the disease, no treatment has been proven to prevent the formation of amyloid plaques. Only the drug developed by the US company Biogen was approved, in 2021, by US authorities, but its interest is still highly contested within the scientific community.

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Should we reject this hypothesis completely? No, say some researchers, who rather point to a rebalancing of knowledge. British neurologist Tara Spear-Jones said: “There is still a lot of evidence of interest in the amyloid cascade hypothesis in explaining the pathogenesis of Alzheimer’s disease.” “But amyloid is far from explaining everything.”

One way to reconcile these situations 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 by European researchers at the end of 2021, who reviewed nearly 200 studies of Alzheimer’s disease and then published their conclusions in Nature Reviews Neuroscience.

Three Alzheimer’s diseases instead of one?

These researchers, led by Italian Giovanni Fresoni, propose dividing Alzheimer’s disease into three main categories. In the first, the amyloid cascade will be the main mechanism. But this may represent a minority of patients, often with an early form before age 50, in whom the role of a particular genetic mutation appears to have been established.

On the other hand, the latter category, in which the role of amyloid plaques is the least exciting, will concern by far the largest number of patients: about half. Three Alzheimer’s diseases instead of one? The researchers concluded that this new perspective could “accelerate the development of strategies to prevent and treat Alzheimer’s disease.”

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