Bart de Strooper, biologist: ‘If we don’t get a treatment for Alzheimer’s, it will be a global disaster’

Biologist Bart De Strooper, one of the world’s leading experts on dementia, makes a grim prognosis. If humanity does not create an effective treatment against Alzheimer’s soon, very soon, the future will be a disaster. An international consortium has estimated that the number of people with dementia will triple in the next quarter-century, exceeding 150 million. “Who will take care of them?” asks De Strooper, who was born in the Belgian town of Tielt.

The German psychiatrist Alois Alzheimer described the first case of the disease that bears his name in 1906. More than a century later, the scientific community still does not understand the exact mechanisms of dementia. Almost three decades ago, De Strooper discovered a form of molecular scissors that gives rise to amyloid, the protein substance that builds up in the brain, which has historically been blamed for Alzheimer’s. But the Belgian scientist from the Leuven Center for Brain and Disease Research argues that amyloid is rather a trigger, causing an inflammatory reaction in brain cells. Once started, this reaction is unstoppable, says the biologist, which is why the new drugs that eliminate amyloid fail to prevent dementia.

De Strooper’s laboratory has just created mice with 100,000 human neurons embedded in their brains, in order to illuminate the enigmas of the disease. At 64 years of age, the researcher still runs nine miles, but he stresses that exercise is not a miracle treatment: two out of every three cases of Alzheimer’s depend on the genetic lottery.

Question. Your mice with 100,000 human neurons obviously do not have a human gaze.

Answer. No, absolutely not. People fantasize, but these mice basically look normal. A human brain has about 100 billion neurons, so 100,000 cells is not going to make anything which comes even close to it.

Q. But a mouse only has 70 million neurons in its brain. So 100,000 human neurons is something.

A. Yes, but let’s think about a country of 70 million people and a small city of 100,000 inhabitants. That’s not going to have a big impact. A few integrate into the brain, but they just act like mouse neurons. Other human neurons form a small clump, somewhat isolated from the rest of the brain.

It is as if you make a network of computers and they are all from Apple, but you put another one from Hewlett Packard in the middle. The result will be the same. It’s nothing spectacular. But the science we can do is spectacular, because in these mice we can make amyloid plaques, like in Alzheimer’s. Mouse neurons do not react a lot, but human neurons develop the whole pathology of Alzheimer’s until they die. It is a fantastic model. The problem is that the brain of a mouse is like this [he makes the gesture of picking up a pea with two fingers] and the brain of a human is like that [he uses both hands to lift an imaginary brain]. So, of course, it’s not a perfect model. The cancer field is decades ahead of us, because it receives much more funding. They have specific drugs against this necroptosis [cell death with inflammation] and we are testing them in our mice.

Q. Do they work?

A. We will know in a year. We need to wait and then we will open the brain. If it works, it’s probably going to be a pill. It’s important for people to realize the complexity: we have the anti-amyloid drug and we have this potential of protecting neurons where they are dying. The big question is: will it be enough? We have a preliminary study that shows a slight effect on maintaining memory in these mice. It’s not spectacular, but a slight effect is good news.

Q. Do you think human neurons should be introduced into monkeys?

A. Good question. When we talk about animal experiments, it’s like all animals are the same and we don’t care. A mouse has a stringent regulation which I think is ridiculous when you put it into perspective. If a restaurant has mice in the cellar, they are killed. There is no ethical question. On the other hand, when we do an experiment on a mouse, minimizing suffering, we have to do a pile of paperwork. We need to have reasonable rethink about this regulation. Monkeys are closer to humans and I think the legislation should be more stringent. At the moment, I think I can answer most of my problems with this humanized mouse model, so I’m not going to use monkeys. But in other types of experiments we will need to use monkeys. If it is not in Europe, I will have to move outside Europe.

Q. What kind of experiments?

A. Well, we have developed an antisense oligonucleotide [a kind of genetic band-aid] to treat a specific mutation in Alzheimer’s disease. It works in patient cells in the laboratory and we are starting to get information that it works in our mouse. But we cannot inject these oligonucleotides into a human being without having first tested it in a species which is close to us.

Q. Will you have to do it in China?

A. There’s still monkey experiments in Europe, so I hope we can do them here. That is the conundrum. If you do them in Europe, you determine the conditions. However, if you ban them here, they will still continue in China, Japan and the United States, and you will no longer have a say in the matter. And if they find a drug against Alzheimer’s in the United States or China, thanks to experiments on animals that you have banned, what hypocrisy would it be to allow those drugs to come to Europe to treat our Alzheimer’s patients! The animal activists’ argument is that we don’t need animal experiments anymore. There is nothing further from the truth. One day I spoke on the radio and received a wave of hate on social media, they told me that what I was doing was absolutely unethical and that I should do experiments on my kids. I wonder what they do when a restaurant owner kills a mouse. The attacks were completely out-of-line.

“The day may come when it will be possible to perform neuron transplants in people with dementia.”

Q. There are surely scientists in China who are already thinking about putting human neurons in the brain of a monkey.

A. Maybe, but it’s not so easy. And we inject human neurons in a mouse to bring it closer to humans. The monkey brain is already much more similar to the human one, I see no reason to humanize it, taking into account the difficulties. I don’t think they will do that. We do these experiments to understand the disease. And they have changed my mind about therapies. The day may come when it will be possible to do neural transplants in people with dementia. Once you have dementia, it’s too late to cure the neurons, but if you can replace some of the ones that have disappeared, you might be able to restore your cognitive abilities. That’s what we’ve seen in mice.

Q. A transplant of neurons from another person?

A. No, from yourself. You take a skin or blood cell. You make a stem cell [capable of becoming any type of cell in the body] from it. You differentiate that to a neuronal precursor and transplant it in the brain. There it grows, it makes connections and it restores the circuitry and thinking. That’s the theory. In Parkinson’s, there are already clinical experiments underway: transplants of neurons in the substantia nigra [a region of the brain stem implicated in Parkinson’s]. I never thought it would be possible in Alzheimer’s, because it is a diffuse disease, while Parkinson’s has a very specific goal to restore. However, it has now been shown that these neurons can integrate in the circuitry of the brain, especially with the experiments of my colleague Pierre Vanderhaeghen. Theoretically it is possible to treat patients with their own neurons. You could transplant your own neurons into your brain.

Q. The technical name of your animals is human-mouse chimera. Chimeras were monsters from ancient myths. What would you say to people who think you are creating monsters?

A. I would ask them to look at what we are doing. This is not Frankenstein, we are simply trying to understand the disease, not make better or different things. It’s about understanding how human neurons get sick and seeing what we can do to prevent it. If you want to say that’s a monster, that’s your way of thinking. I don’t oblige you to do the experiments and I also don’t oblige you to take any medication that may come out of this research.

Q. You are 64 years old. Do you think you will live to see an effective treatment for Alzheimer's?

A. Without a doubt. We already have the first effective treatments authorized in the United States, but I don’t know if they will be approved in Europe, because they are quite expensive and the results are not magical.

Q. Are you referring to lecanemab, a treatment from the Japanese pharmaceutical company Eisai and the American company Biogen, which eliminates amyloid and delays cognitive decline by 27%?

A. Yes, to lecanemab and donanemab [another similar treatment, from the U.S. pharmaceutical company Lilly, which delays cognitive deterioration by 35%], which will be authorized soon.

Q. And what do you think of aducanumab, the first treatment against amyloid, from Biogen, which was controversly approved in the United States in 2021?

A. Aducanumab has now been abandoned. The clinical trial was very badly done, its results were not convincing and they have never gotten away from that stigma. They used lobbying to get the drug approved. There were also a lot of other mistakes. I think they were very arrogant to ask in the beginning for $50,000 for each treatment. The other two drugs do have an impeccable drug report. There are side effects, but they are known risks. The results are not spectacular either, but what do you want with the first drug? I was a doctor in Paris when AIDS came up and no one knew what to do. The first pills arrived and you had to take them four times a day to gain a week of life. Two decades later, AIDS has basically been cured. These first Alzheimer’s drugs are the beginning of a new era. And we need more incentives to find cheaper drugs that lower amyloid, even if we don’t immediately see the slowing down of dementia. We need to give a carrot to the industry because billions of investment is needed to get such a drug. We need governments to promise that if a drug like this is available, they will approve it. That will accelerate research tremendously.

Q. Does the idea of developing Alzheimer’s scare you?

A. Yes, it scares me. My mother died from Alzheimer's.

Q. What will happen if we don’t discover an effective treatment in the next 30 years?

A. It will be a disaster.

Q. It is estimated that 150 million people will be living with dementia in 2050, almost triple the number now.

A. It is a disaster worldwide, but let’s look at our countries: Spain, Belgium, England, France. They have a very good health system and an aging population. Who is going to take care of all these people? We already need to take the best nurses and caregivers from poor countries to take care of our aging population. Triplicate that. I can only speak in terms of disaster if we don’t get some treatment. I’m 64, but I’m still running 15 kilometers. Prevention is very important for dementia in general, but not so much for Alzheimer’s. We’ll need medication, something you can take when you’re 60 that blocks the amyloid, to postpone the disease for five or six years, which would be perfect. Otherwise, I don’t see how we will move forward as a society.

Q. Is Alzheimer’s research underfunded?

A. It’s extremely underfunded. In Europe, it’s a disaster. I will never say that less money should go to cancer, I think it gets what it needs. What I’m saying is that dementia should receive the same.

Q. What is the difference between Alzheimer's funding and cancer funding?

A. Cancer receives 15 times more, in money and in everything. There are about 55 million people with cancer in the world. And there are about 58 million with dementia. It is a problem of the same magnitude, but in the databases there are 4.5 million studies on cancer and barely 350,000 on neurodegeneration. About 15 times more.

Q. A Spanish scientist, Pío del Río Hortega, discovered microglia (the cells of the nervous system that defend it from attacks) in 1919.

A. He is our Pope.

Q. What is the role of microglia in Alzheimer's?

A. It is crucial. Amyloid is a trigger, but then there’s how microglia and other cell types may react to that trigger. Microglia see amyloid as a kind of infectious agent and fight against it. By doing so, there is inflammation, which is not very healthy for the brain. Microglia send signals to other cells: “Come and help me!” You get a chronic cellular reaction which, in my opinion, is initiated by the microglia. It’s the central player. A large part of my research now focuses on microglia. I believe that we will discover drugs capable of attenuating this inflammation.

Q. A Spanish scientist once argued that thinking that amyloid is responsible for Alzheimer’s is like arriving at a crime scene and believing that the blood committed the murder. What do you think?

A. Maybe it was logical 10 or 15 years ago. I understand why the scientists is saying that, but it doesn’t take genetics into account. There’s absolutely clear evidence that if you have a problem with amyloid, you can die. It’s like arriving at a crime scene, seeing a gun, and coming to the conclusion that that gun is probably the cause.

Q. Is amyloid the gun?

A. Amyloid is the gun, yes. But it is more complex than a gun, because with a gun you shoot and the patient is dead. In real life, the amyloid is there and then there’s a reaction, an inflammation. We need to avoid simplisms. It is a chronic disease, like cancer. The body, in youth, is able to maintain amyloid at healthy levels. In old age, our resistance decreases and this becomes a problem. It is a very slow disease. A study by the Alzheimer’s Association in the United States showed that, if we find a drug capable of delaying the onset of dementia by five years, you will keep the number of people with the disease at the number we have now. We could stabilize the problem, which would be great. I’m optimistic. That is our first aim: to delay the disease for five years.

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