Science

Alzheimer’s: “It is vain to hope to treat all patients equally”

No progress in the fight against Alzheimer’s? This idea is opposed by Prof. Marie Sarazin, Head of the Department of Neurology of Memory and Language at the Hospital of St. Anne in Paris. Of course, there is still no treatment that would slow down this pathology or stop it. But despite mistakes, debates and ups and downs, the last decades have brought much knowledge that points the way forward into the future. On the occasion of the World Day dedicated to this disease, which affects a million people in France, this neurologist describes them in detail for L’Express. Service.

L’Express: Suspicions of fraud in scientific publications rocked Alzheimer’s research this summer. Do these manipulations call into question what they think scientists and doctors know about this pathology, and in particular about the involvement of the amyloid protein that forms the famous “senile plaques” in the brains of patients?

Professor Marie Sarazin: Neurodegenerative diseases are characterized by abnormalities in certain brain proteins: they are deformed, they aggregate abnormally. This contributes to neuronal dysfunction and the symptoms we know of—memory disorders, as well as language, behavior, visual perception, etc. In Alzheimer’s disease, we are talking about the amyloid protein that accumulates around neurons, and the tau protein that multiplies inside these nerve cells.

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Discussions this summer focused on very difficult points regarding the exact role of protein subtypes. At the same time, the “amyloid cascade” is not questioned. According to this theory, senile plaques will accumulate for years without any clinical signs. However, this will eventually lead to abnormalities in the tau protein that will be responsible for the symptoms. But it doesn’t matter, in fact: doctors and patients primarily hope to be able to detect the disease very early, even before the first violations appear, in order to successfully stop its development.

At the same time, all the treatments that have been clinically tested in recent years have been aimed at eliminating these amyloid plaques in the brains of patients, and they have all failed …

Their failure was not unexpected. We have long known that the amount of amyloid proteins in the brain of patients does not correlate with clinical signs or their severity. So it’s not surprising that when we try to “clear” these plaques, we are disappointed in the results. This does not mean that amyloid protein does not play a role. In familial forms of Alzheimer’s disease or in people with Down’s syndrome, genetic mutations lead to the early onset of this disease, and all these mutations are found in genes associated with the overproduction of this protein. Above all, these failures show us that we need to better understand its effects and, in particular, its association with the tau protein.

Moreover, it is possible that these drugs give long-term results. In the United States, the health authorities refused to reimburse the cost of one of these products, but nonetheless asked the laboratory to conduct a long-term follow-up of the treated people to see if there might be a decline in the course of the disease after four or five years.

The big idea in recent years has been to give them as soon as possible, even as a preventive measure. What about?

These drugs were offered to high-risk subjects, especially those with familial disease. Initial results are disappointing, but testing continues. They are difficult to perform, since in this case it is a rare disease that few patients suffer from. But it’s not all bad: the work done in recent years shows us at least that we can develop monoclonal antibodies that can act inside the brain. This is a key moment for the future.

“Understanding why proteins progress in the brain”

Moreover, this form of immunotherapy alone may not be enough. Our immune system is indeed made up of antibodies, as well as lymphocytes, which are also involved in the “cleansing” of abnormalities in our body. Perhaps both are important for proper plaque removal. This is a hypothesis that we are going to test in Paris after the work of immunologist Guillaume Dorothy from the Hospital Saint-Antoine (AP-HP) to see if we can enhance the effect of antibodies in other ways. This will include modulating the immune system with drugs to give it a favorable profile. A pilot study will start soon, thanks in part to funding from the Medical Research Foundation, with a very small number of patients.

Shouldn’t we also target the tau protein?

This protein is indeed highly correlated with clinical signs. When a patient loses memory or language, we see on brain imaging that the protein builds up, especially in the affected areas. The problem is that tau is located directly inside the neurons. So the drug has to go to the brain and then to these cells. Another difficulty is that this protein not only has a pathogenic effect, but also performs many functions. The challenge is to prevent its accumulation without completely eliminating it. Tests are ongoing, but the first known results at this stage do not seem very impressive.

There is also a lot of work on why proteins progress in the brain. Lesions begin in one place, but then they spread gradually, in proximity. By better understanding the mechanisms at work, we could stop this spread.

Inflammation is also often cited as the cause of disease. What do we know today about the role of our immunity?

That’s a very difficult question. The immune system has many processes, many different cells, which can have a positive or negative effect depending on the stage of the disease and the patients. It’s a bit like Dr. Jekyll and Mr. Hyde. But in fact, we see that some patients have very aggressive forms of the disease, and others less, probably because of their immunity.

“It is possible that these drugs will give a lasting result”

What I think is important at this stage is that this complexity shows us first of all that it is certainly useless to want to treat everyone the same. Of course, it is not hard to see that for a pharmaceutical laboratory, finding a unique cure for a very common disease would be a jackpot. But the more we know about this disease, the more we understand that it is a heterogeneous disease, with subgroups of patients that differ in the biological mechanisms involved.

We must now focus on identifying these patient groups and then providing them with appropriate treatment when available. It’s a bit like cancer: the tumor is biopsied to determine the best therapeutic strategy. In Alzheimer’s disease, abnormal proteins are present, as well as the severity of deposits, their topography, reactions around them, at the level of immunity, as well as synapses. Perhaps by trying to treat everyone equally, we are on the wrong track. When I started teaching, I said it was a homogeneous disease. Now I’m saying the opposite.

Until effective treatments are available, what do you say to people who are concerned about memory loss: do they still need to be diagnosed?

Of course, this is very important. Memory problems may be related to depression, vascular disease, or other causes. It’s not just Alzheimer’s. And if this is proven, then this makes it possible to explain the symptoms, prescribe accompaniment, it is possible to offer symptomatic drugs.

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These products have unfortunately been delisted in France, although they have reduced patient confusion and anxiety. In the United Kingdom, health authorities have also re-evaluated these products and concluded that these products can delay the admission of patients to a health facility. Of course, they do not prevent the progression of the disease, but they still bring benefits to patients.

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