'We suspect Alzheimer's begins as early as your 40s'

This article was written by Joël De Ceulaer for publication in De Morgen as part of the series 'Living Longer'.

What do we know about Alzheimer's and other forms of dementia? Can we prevent them? Is medication on the way? A conversation with experts Bart De Strooper and Rosa Rademakers on dying neurons. 'Our brain is more complex than the cosmos'.

"The brain is a fantastic organ," says Bart De Strooper. "When I give a talk, I always use this comparison: there are eight billion people in the world, and more than 10 times as many neurons in your brain. These are constantly active, regulating your heartbeat, your emotions, while you are reading, sitting up, or talking - during this conversation, our brains will constantly change, because new connections are constantly being made. Our brain is more complex than the cosmos."

De Strooper is one of the pioneers of research Alzheimer's disease, the first known form of dementia described by German Alois Alzheimer in 1906. The researcher found that accumulations of the amyloid protein led to irreversible brain damage in deceased patients. In the late 1990s, De Strooper discovered that the presenilin protein plays an important role in the formation of those amyloid plaques. This did not lead to a treatment, but De Strooper is still at the forefront of research. "We are making a lot of progress in recent years."

Rosa Rademakers - successor to Christine Van Broeckhoven, the other Flemish pioneer in dementia research - is also among the top international researchers in this field. De Strooper and Rademakers know each other well. "When she was in America, I offered Rosa a place at my center," he says. "She did not accept, because she ran a lab in the US and was very happy there. Which, of course, I understood."

In a nutshell

Rademakers is Dutch, and did her PhD with Van Broeckhoven. She ran her own lab in the US for 12 years. Her research is also groundbreaking. When she received the offer to take over her center upon Van Broeckhoven's retirement in 2019, she did not hesitate. "I was happy to return, also because my husband is Belgian and both our families live here," she says. "It seemed right for us to let the children grow up here. Although I have to say that in America everything goes much faster in science, and there is much more money."

De Strooper, too, could have worked just about anywhere in the world. "But I always chose family," he says. "I wanted to stay here. Although America is indeed more attractive. In Europe, people don't like to take risks, and you have to be prepared to do that sometimes. Everything here is buried under regulations, which is sometimes frustrating. Fortunately we have had VIB (the Flemish Institute for Biotechnology) since 1995, otherwise I might have gone abroad. At VIB the emphasis is on excellent research with a link to industry. Both my lab and Rosa's belong to VIB."

Let's get straight to the point. Do you die of or with Alzheimer's?

De Strooper: "That's a theoretical discussion. You don't die acutely from Alzheimer's, but in the UK it is reported as the cause of death, which I think is right. You get so weakened that you die. You may even wonder if, at the end, you are not already dead while you are still alive."

Rademakers: "Indeed, you cannot keep walking around with Alzheimer's. You do die from it. Eventually, you can't breathe, you can't eat - you die as a result of deterioration."

De Strooper: "In Wales and England, it has been the leading cause of death for several years. If it was recorded as a cause of death in Belgium, it would probably be the same here. Alzheimer's is a bigger medical problem than cancer. There are more patients, no drugs yet and the number of people suffering from it is likely to triple by 2050."

Rademakers: "And there a,re already about 200,000 patients in Belgium."

Rosa Rademakers

born 28 June 1978 in Amsterdam - professor at the University of Antwerp - led a laboratory at the Mayo Clinic in Jacksonville (US) - has had her VIB lab at UAntwerpen since 2019, succeeding Christine Van Broeckhoven

For the record, Alzheimer's and dementia are not synonyms.

De Strooper: "No, definitely not. We should not just talk about Alzheimer's but about neurodegenerative diseases, which are caused by the degeneration, the dying off of brain cells."

Rademakers: "We should indeed open up the debate. Most people with neurodegeneration suffer from complex disorders, with many different proteins accumulating in the brain. There are various types, such as young-onset dementia, Parkinson's disease, frontotemporal dementia, and Lewy body dementia... There are several proteins that can precipitate and accumulate between neurons or become entangled so that brain cells eventually die. Amyloid and tau are two of the best-known and typical of Alzheimer's. But there are others."

De Strooper: "Look at it this way: in the brain and brain stem, any area can undergo degeneration, with brain cells dying off. Since the symptoms can vary greatly, people use many different names in the clinic. But the core of the problem is the same: neurodegeneration. This is also the case in the disease ALS, amyotrophic lateral sclerosis (which affects the muscles, ed.). Rosa discovered this: genes that lead to frontotemporal dementia also lead to ALS. Yet no one will subsume ALS into dementia."
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​Rademakers: "The genetic defect is the same, but the disease is completely different, and that depends on where the protein accumulates: in the frontal and temporal cortex or in the spinal cord. In some families, only one disease occurs, in others both, and often patients even have both diseases at the same time. We don't know why. There will be additional genetic factors."

De Strooper: "Doctors focus on the symptoms, but we need to get away from that. As researchers, we are obsessed with the underlying mechanisms. Symptoms do not always indicate dementia either. If the back of the brain is affected, the patient initially presents with visual problems."

Which makes one think there is something wrong with the eyes.

De Strooper: "Exactly. And tests show that there is nothing wrong with the eyes. The problem is that the patient can no longer process the visual information in the brain. I would say compare it to cancer, which also occurs in many places, and the symptoms differ greatly. Yet the disease is looked at and investigated in the same way. We have also reached that stage in the study of neurodegenerative diseases."

Rademakers: "In frontotemporal dementia, neurons die off in the frontal and temporal cortex. The symptoms you then see are loss of language and changes in personality and behavior. Patients lose their filter: they make unwanted advances at work, they lie on the sofa all day, or they behave socially inappropriately."

De Strooper: "They suffer from loss of decorum, as it is called. In Alzheimer's, it is mainly the hippocampus where the damage occurs, affecting memory."

Rademakers: "So it involves different proteins - apart from amyloid and tau, we also know about TDP-43, among others - and different areas in the brain where the damage occurs. Sometimes one protein is involved, sometimes several at once. For researchers and doctors, it is important to know which proteins are involved, because that tells us something about the cause and possible future treatments. For example, it is possible that Alzheimer's proteins damage the frontotemporal lobe, and then you have a patient with Alzheimer's disease who behaves as if he has frontotemporal dementia."

I have seen the lesser-known Lewy body dementia, in which the cerebral cortex is also affected. This starts with hallucinations and leads to death fairly quickly, within a few years. Which you can see as a form of mercy.

De Strooper: "Yes, it's an odd thing to say, but I understand what you mean."

Rademakers: "Lewy body dementia involves the same protein as in Parkinson's disease, only it deposits in different places. The hallucinations are typical symptoms."

De Strooper: "Lewy body dementia is a terrible disease, but life expectancy is indeed short. With Alzheimer's, the average life expectancy after diagnosis is still eight years. But by then it has often been going on for 20 years. That's one of the big discoveries of the last few years: we suspect that Alzheimer's starts as early as your 40s. That's our big dispute with clinicians, who only speak of Alzheimer's when symptoms appear. We know it starts earlier."

How exactly?

De Strooper: "With cells that inflame and die, without you noticing. The brain, with its hundred billion brain cells, is very plastic. If a connection is lost, another one is made. That plasticity does deteriorate: at eighteen, you can learn a new language much more fluently than at fifty. But the loss of cells is smoothly absorbed by other neurons for years in Alzheimer's."

Rademakers: "That's why it takes so long for symptoms to appear. As we age, we naturally lose neurons. But that's a normal process that shouldn't be a problem until, say, age 80. It is only when there is a problem and bad proteins accumulate that things speed up. Normally, the brain's lysosomal system can clean up these proteins, but as we get older or have genetic defects, this system may not work as well. At age 40, it's unlikely that you'll experience any symptoms yet."

De Strooper: "Clinically, that is the silent phase. So the ultimate goal is to prevent Alzheimer's, and other neurodegenerative diseases."

Can you screen people at 40?

Rademakers: "That's not affordable for the entire population, of course. And we can't see much through medical imaging at that early stage. The hope is to be able to detect the first signs of disease in the blood by identifying signs of dying brain cells. The neurofilament protein is a possible candidate for this and is already being used in experimental studies in families with frontotemporal dementia."

De Strooper: "Previously, one could only tell after death that a patient had the disease. Now, we can use PET scans to make a good diagnosis, but not at that early stage. We can also look for traces in the spinal fluid. But in the last two years, people have been working on a blood test, also for Alzheimer's. But note: please put in your article that people should not yet run to the doctor for such a test, because we still have a year or two to go."

Is the press too eager to announce 'breakthroughs'?

De Strooper: "Absolutely. There is a lack of patience and knowledge. This often makes me feel very uncomfortable. When I read a scientific article in the newspaper, I sometimes think: so this is how they interview politicians too. People sometimes accuse scientists of not communicating well and often enough, but the media should also play their educational role. So don't write that a breakthrough is imminent for an early blood test, as we still need to convince doctors themselves of the importance of such a test in the early stages."

What kind of test would already be possible?

De Strooper: "You could do a memory test at signs of forgetfulness. If there are reasons to be worried, you could investigate further. If nothing seems wrong, you can repeat the same test ten years later and compare it with the first one. Such a personalized test is better than looking for deviations from the average. Intelligent people will automatically score better, so you can only see the problem when you compare with the same test in the same person ten years earlier."

Rademakers: "I completely follow that. If you compare people who are very intelligent with the whole population, it doesn't say anything."

De Strooper: "You notice if someone drops from, say, 10 percent to 5 percent in such a test. But for those who drop from 95 percent to 90 percent, there seems to be nothing wrong. In any case, we need to move away from condoning memory problems. Because we still do that. Of course, your memory deteriorates in old age, but we need to take complaints seriously."

Rademakers: "Because we are quietly moving towards possible therapies, it is important that we get there in time."

Bart De Strooper

born 29 January 1960 in Tielt - professor at KU Leuven and University College London (UK) - leads a research group at the Flemish Institute of Biotechnology (VIB) - has been director of the UK Dementia Research Institute (London) since 2016

What therapies are on the way?

De Strooper: "There is an antibody-based medication that does seem to work: there is scientific evidence based on phase 3 clinical trials, which is the gold standard. There are still many nuances, and it is only a first step, but you can call that a breakthrough. We have already tried several keys to break down the bad proteins, and we felt the click with the drug Lecanemab."

Is that medication already available?

De Strooper: "In America, it is. The therapy costs $25,000 a year. In Europe, we are only at the application stage. The regulatory mess, right."

Can there be genetic intervention?

De Strooper: "The purely genetic forms are rare. In Alzheimer's, five out of 10,000 cases, which is 0.0005 percent, involve one specific genetic mutation. So you don't need to panic too quickly if your father or mother has or had it."

Rademakers: "I do genetic research on families with patients with young-onset dementia. If you see in a family that in each generation half get the disease, you can assume that one genetic defect is enough to cause the disease. We look for those defects. But monogenetic forms are rare indeed. If 20 different genetic defects cause the disease, it will not be familial."

De Strooper: "We often talk about pure heredity in the case of one genetic mutation."

Rademakers: "Those are also the easiest to detect. And in those cases, you can also develop a therapy to treat people who are carriers of the defect but are not sick yet. This approach is being tested in the genetic forms of ALS and frontotemporal dementia that we discovered: with synthetic pieces of genetic material that bind to the bad pieces. It is already successful in babies with SMA, spinal muscular atrophy. Normally, those children die before the age of two. For another rare form of ALS, a drug - based on the same technology - was approved under special conditions in Belgium last year."
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​De Strooper: "Keep in mind that our field is 20 years behind cancer research. But these are first, important steps. And things can move fast: look at the treatment of AIDS, for example. That started slowly, but suddenly went very fast."

Much more money should go to research?

De Strooper: "Let me first say that more money should also go to cancer research. It is not a competition in that sense. But look at the numbers. There are 55 million people with cancer and 58 million people with dementia worldwide right now. So, the problem is of roughly the same magnitude. However, if you go and look at all the publications of the last hundred years on neurodegenerative diseases, you will find roughly 350,000. If you look at the publications on cancer, you find four and a half million."

How come?

De Strooper: "In 1978, the global war on cancer started. The taboo fell. Until the 1990s, people still talked about 'a lingering disease' you died from. The taboo about dementia is still there. We need to break that, too. This research should be given the same priority as cancer research. All European governments should come up with more money, but I also think the American system of charity works: rich people investing in research because their family was affected by the disease, for example."

Rademakers: "That is indeed common in the US: philanthropists bringing researchers together to make faster progress. As for the taboo, that is decreasing anyway. There was that wonderful program "Restaurant Misunderstanding" on national television with people suffering from young-onset dementia. So, there is an evolution. But there is still room for improvement, of course. What also plays into the lead that cancer research has: cancer is simpler. You can take a tumor out of a patient and examine that. You can examine the brains of patients with dementia only after their death when the most vulnerable cells are already gone."

As an aside: that we only use part of our brains is a misconception, I suppose?

Rademakers: "They used to think that about our DNA too, that only three percent was important. Now it turns out that all those other pieces play a crucial role in regulating that three percent."

De Strooper: "There is not one brain cell too many in your head. Just know that."

Are you afraid of becoming demented?

De Strooper: "Of course. Since I have been studying Alzheimer's disease, I have been afraid of getting it. Especially now that I have also seen it in my mother. With her, by the way, it started with hearing problems: she had trouble talking on the phone, not because she could no longer hear the person on the other end, but because she no longer understood them. It was not due to her hearing but the processing of information in her brain. Over 85, one in three people get Alzheimer's. My big fear is that I will get it before the age of 80."

Rademakers: "I'm more afraid of getting cancer, but maybe that's because I'm only 45. Being in this field of study doesn't make my fear any worse. I might as well have been in cancer research. I was fascinated by genetics and wanted to do a PhD with Christine Van Broeckhoven, which is how I got into this research."

How does it feel to make a world discovery, which you both accomplished?

De Strooper: "Like being a footballer scoring the winning goal in the Champions League final."

But your discovery did not immediately lead to the expected breakthroughs.

De Strooper: "That's part of science. If you are driven, you don't let that discourage you. Because we found the protein that acts as a scissor for amyloid, we thought the treatment could be to block that scissor. Everyone thought it was going to work. However, the problem is that you can't block that scissor, because it is needed to cut other proteins, which do thousands of other things. But it was a substantial discovery nonetheless."

Rademakers: "Absolutely. A discovery that immediately put genetics at center stage. Now, in recent years, new developments are moving very fast again. The fact that antibodies appear to work is super important. And the latest technology allows us to study individual cells."

What about artificial intelligence?

De Strooper: "That is obviously the next step. Thanks to bioinformatics, we can study information from all cells at once and recognize patterns that you cannot see as a human being."

Rademakers: "In my lab, many people already work exclusively on computers. You used to look for a needle in a haystack, and now you can systematically analyze huge amounts of data."

De Strooper: "I would so love to be a young person again. The field is becoming incredibly interesting. The current momentum is promising for people who are young today, both in terms of prevention and medication."

In Parkinson's, brain cells also die. There would be a link to pesticides: is that a correct research avenue?

De Strooper: "Pesticides are definitely a cause for concern, absolutely. In the 1980s, we already knew that a certain poison present in some drugs caused Parkinson's disease. We are still using that drug to cause Parkinson’s in tests on mice."

Animal testing: a delicate subject.

De Strooper: "We will never be able to do without it. Animal testing is the only way to really prove causal relationships. It is strange that nobody makes a problem of poisoning mice if they are in your house, but are against animal testing in scientific research. The logic of that escapes me. If animal testing is ethically problematic, what are we going to say when we make pieces of the human brain with stem cells? Suppose we make a hippocampus: are we allowed to do research on that?"

Rademakers: "In my lab, we also still need mice. I don't like working with those animals, mind you. But we do indeed need them. And we have to comply with very strict rules. Every step has to be thoroughly justified."

De Strooper: "Europe wants animal testing to be phased out, and the Flemish government is going along with that. If that happens, we can shut down medical research in Europe."

Another ethical question: do you think the law on euthanasia should be extended to people with dementia? That you can put in a will that you want euthanasia at a certain stage of the disease? Now, that will only apply if you are in an irreversible coma.

De Strooper: "I think you have to respect the person you were at the time you wrote the will."

Rademakers: "The point, of course, is that euthanasia should then be performed on people who no longer know anything about anything. It could be that people with dementia gradually take a different view of euthanasia. That is difficult to research."

De Strooper: "I think you have to respect what someone asks. The legislation in Belgium is good. There is what I would call Hugo Claus' loophole: with him, people waited just long enough for him to put another cross as a signature, as it were. What someone thinks or feels when he or she is fully demented always remains a matter of interpretation."

Let's end on a positive note. What can we already do ourselves for prevention?

De Strooper: "Healthy living and exercise. Everything that cardiologists recommend you do also applies to dementia."

Rademakers: "We don't know the ins and outs of it yet, but we indeed know enough to definitely encourage people to exercise and eat healthy."

And fill in a lot of sudokus?

De Strooper: "No, that doesn't amount to anything. If you just live, you use your brain much more intensively than if you fill in sudokus or solve mathematical equations. If you like that, it's fine. But don't think it will help you prevent or delay Alzheimer's. Social contact is more important."

Rademakers: "True. Sitting alone in your little flat all day is not good. Get among people. To stimulate your brain, you just have to live."

This article was written by Joël De Ceulaer for publication in De Morgen as part of the series 'Living Longer'.

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