Alzheimer's disease: "It is vain to hope to treat all patients in the same way"

No progress against Alzheimer’s disease? Pr Marie Sarazin, head of the neurology of memory and language department at Sainte-Anne hospital in Paris, protests against this idea. Certainly, there is still no treatment that would slow down this pathology, or stop it. But despite the missteps, the debates and the twists and turns, the last decades have brought a lot of knowledge that shows the way forward for the future. On the occasion of the world day dedicated to this disease which affects a million people in France, this neurologist details them for L’Express. Maintenance.

Suspicions of fraud in scientific publications have shaken research on Alzheimer’s disease this summer. Do these manipulations call into question what scientists and doctors think they know about this pathology, and in particular the involvement of the amyloid protein, which forms the famous “senile plaques” in the brain of patients?

Professor Marie Sarazin Neurodegenerative diseases are characterized by abnormalities in certain brain proteins: poorly formed, they aggregate abnormally. This contributes to the dysfunction of neurons and the symptoms that we know – disorders of memory, but also of language, behavior, visual perception, etc. In Alzheimer’s disease, we talk about the amyloid protein, which accumulates around neurons, and the Tau protein, which multiplies inside these nerve cells.

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The discussions this summer focused on very complex points, concerning the exact role of protein subtypes. The “amyloid cascade” is not called into question for all that. According to this theory, senile plaques would accumulate for years without there necessarily being any clinical signs. However, this would eventually lead to abnormalities in the Tau protein which would be responsible for the symptoms. But no matter, in reality: what doctors and patients hope above all is to be able to detect the disease very early, even before the appearance of the first disorders, in order to then succeed in stopping its evolution.

At the same time, all the treatments in clinical trials in recent years have aimed to eliminate these amyloid plaques in the brains of patients, and they have all failed…

Their failure was no surprise. We have known for a long time that the quantities of amyloid proteins in the brain of patients are not correlated with the clinical signs or their severity. So it’s no wonder that when trying to “clean up” these plaques, we are disappointed with the results. That’s not to say amyloid protein doesn’t play a role. In the familial forms of Alzheimer’s disease or in people with Down syndrome, genetic mutations lead to the early onset of this pathology, and these mutations are all found in genes linked to the overproduction of this protein. Above all, these failures show us that we must therefore better understand its effects, and in particular its links with the Tau protein.

Moreover, it is not completely impossible that these drugs produce results in the long term. In the United States, the health authorities refused to reimburse one of these products, but they nevertheless asked the laboratory for a long-term follow-up of the people treated, to see if there could not be, after four or five years, a decline in the course of the disease.

The big idea in recent years was to give them as soon as possible, even in prevention. What about?

These drugs have been offered to subjects at high risk, particularly in the familial forms of the disease. Initial results are disappointing, but testing continues. They are difficult to carry out, because in this case it is a rare disease, which affects few patients. But all is not negative: the work carried out in recent years shows us at least that we know how to develop monoclonal antibodies capable of acting inside the brain. This is a key point 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, but also of lymphocytes, which also participate in the “cleaning” of anomalies in our body. Perhaps both are important for proper plaque removal. This is a hypothesis that we are going to test in Paris, following the work of immunologist Guillaume Dorothée, from Saint-Antoine Hospital (AP-HP), to see if we can reinforce the action of antibodies by d other means. This would involve modulating the immune system with drugs to give it a favorable profile. The pilot study will start soon, thanks in particular to the financial support of the Foundation for Medical Research, 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 the patient loses memory or language, we see on brain imaging that the protein accumulates especially in the areas concerned. The problem is that Tau is found directly inside neurons. The drug must therefore pass into the brain and then into these cells. Another difficulty, this protein does not just have a pathogenic effect, it also has multiple functions. The challenge is to prevent it from accumulating, without eliminating it completely. Trials are underway, but the first known results at this stage do not seem very spectacular.

There is also a lot of work on why proteins progress in the brain. The lesions start in one place, but then they spread gradually, by proximity. By better understanding the mechanisms at work, we might be able to stop this spread.

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

It is a very complex question. The immune system has many processes, many different cells, which can have positive or negative effects 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 not completely impossible that these drugs will produce lasting results”

What seems important to me at this stage is that this complexity above all shows us that it is undoubtedly futile to want to treat everyone the same way. Of course, it is easy to understand that for a pharmaceutical laboratory, finding a unique drug for a very widespread disease would be the jackpot. But the more we know about this disease, the more we realize that it is a heterogeneous disease, with subgroups of patients who are distinguished by the biological mechanisms involved.

We must now focus on identifying these groups of patients and then giving them appropriate treatments when they are available. It’s a bit like with cancer: tumors are biopsied to determine the best therapeutic strategy. In Alzheimer’s disease, there are abnormal proteins, but also the severity of the deposits, their topography, the reactions around them, at the level of immunity, but also of the synapses. Perhaps by trying to treat everyone the same, we are on the wrong track. When I started teaching, I said that it is a homogeneous disease. Now I say the opposite.

Until effective treatments emerge, what do you say to people who are worried about memory loss: should they still get diagnosed?

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

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These products have unfortunately been delisted in France, while they reduced the confusion and agitation of patients. In the United Kingdom, the health authorities have also re-evaluated these products and have concluded that these products make it possible to delay the entry into an institution for patients. Of course, they do not prevent the progression of the disease, but they still brought a benefit to the patients.