Mercè Boada: "We are tightening the net on Alzheimer's diagnosis"

With her husband, psychologist Lluís Tárraga, Mercè Boada laid the foundations for a type of help that did not exist thirty years ago. In the winter of 1991, they made it much warmer for people with dementias like Alzheimer's and their families. They opened a model center for accompanying those suffering from cognitive deterioration. It is the ACE Alzheimer Center Barcelona, of which Boada is medical director. From there, and following the Integral Psycho-stimulation Program (PTI) designed by Tárraga (which is used throughout Spain) they opened the first day center to help these people slow down memory loss, listening to the concerns and fears of their caregivers, attending consultations, and monitoring the evolution of each patient.

Each of them holds a story, a cerebral mystery, a valuable piece in a global hieroglyph that professionals like Dr. Boada and her team wake up and go to bed every day with the desire to solve. Everything they observe, listen to, and measure in each person they attend to, they contrast with what they can see happening inside and around their brain. Every clue they find is a valuable asset in global research.

--- ACE Alzheimer Center Barcelona has contributed 28 of the 1,795 patients worldwide participating in the study that led to the approval of the first drug that slows cognitive decline in early Alzheimer's patients.

--- Yes, Spain included 142 patients, and 20% of these were from us. The study comprised almost 6,000 people worldwide, of whom only 1,795 could enter, 30% of the candidates, because the rest did not meet the conditions. One of them had to be having cognitive impairment or mild dementia, and the other, showing the presence of Beta-amyloid and TAU proteins, precursors ----when there is an accumulation of them--- of Alzheimer's disease, and these had to be found by analyzing their cerebrospinal fluid, the element closest to the brain, which is obtained through a lumbar puncture or a Beta-amyloid PET scan (neuroimaging marker) that visualizes it.

--- You have been dedicated to the study of Alzheimer's and dementias for more than 30 years. Where are we now compared to then?

--- Now we are tightening the net around diagnosis, above all, because we can do it very early, in a very early phase. 30 years ago, it was not an urgent necessity, because we had a clinical diagnosis that we could see, but we had no treatment. At this moment, everything that has been learned has changed the scenario for the better. The disease is today a resounding success; although families and affected people think that we have been helpless and hospitals feel that we are facing an orphan disease without an effective medication, much progress is being made in research. Today, Alzheimer's is a disease of rapid transformation, despite its chiaroscuros.

--- What have been the main advances?

--- Since 2003, we had been focusing on eliminating the Beta-amyloid protein from the brain, believing that the whole problem was centered on it; following the hypothesis known as the Beta-amyloid cascade, all pharmaceutical research focused on it. Until 2023, we did not have a drug to clean the brain of this protein, control its deposition, and offer clinical benefits. Previous drugs cleaned, but did not provide benefit. Other hypotheses have grown as we have failed. We have seen, for example, that if a high dose of these drugs reaches the brain, adverse effects can be seen with the presence of cerebral edema, sometimes with a small white line visible on an MRI; other times, with images that make you shudder, despite causing few symptoms. But this is how we have learned to describe these brain images and to control them by neuroradiologists and neurologists. Now we know how to see other physiological processes that intervene in this type of dementia. One should never think that falling short in a race means you will not get up and win the marathon; perhaps you won't win today, but you will in 4 or 5 years. If we had given up, today we would not be where we are—researchers, the pharmaceutical industry, patients, and their families—we all run together in this long-distance race.

"If we had given up, today we would not be where we are—researchers, the pharmaceutical industry, patients, and their families—we all run together in this long-distance race"

--- Today we can say that we have a drug that offers possibilities for controlling this disease that we did not have until now. This is the great success. We wanted to biologically modify the triggering of the disease. We believe that Beta-amyloid and TAU proteins are always present in an Alzheimer's brain; they are its hallmark. Both have a life of their own, capabilities like a microorganism that deposits, disseminates, and moves through the brain, causing the neuron and its entire environment to stop.

--- Is that how cognitive decline and dementia are reached? --- Yes, because neurons communicate with a wireless phone. Between one neuron and another is what is known as the synaptic space; the wireless thread is neurotransmitters, highly complex chemical substances that carry information from one neuron to another. If this communication fails, the system fails. Externally, we can introduce artificial neurotransmitters; this is what is achieved with the first drugs prescribed for Alzheimer's. But if I don't have neurons to communicate because the disease has destroyed them, there is nothing that can be communicated. The second step is to protect the neuron, something these medications have not done, to ensure that the neuron does not disappear. Hence the need for an early diagnosis, so that the millions of healthy and active neurons that maintain their function, in relation to those that are falling or collapsing, make a positive balance. Thus, treatments will have a better effect, like those we will now have available.

--- Early detection up to what limit?

--- The maximum possible, this is the limit or the no-limit. When the person is in a state of full autonomy, capable of deciding autonomously and making decisions about their vacations, their financial status, they can carry things from home, make phone calls and schedule, or drive, but their cognitive capacity of the brain begins to fail. That is the moment when we would really have to make the diagnosis, and we are achieving it. Approximately 40% of those who come for a diagnosis at our center have the characteristics of mild cognitive impairment, not dementia, that is, they are in the preliminary signs of the disease, in the prodromal state. At this point, the family usually says that they are losing memory because they are getting older, or that they have never had memory, or because now the mother is alone or the father has stopped being a company director, because their world has changed... All this psychoactive context makes us not as brilliant as we are supposed to have been. But being 75 years old today is not the same as 30 years ago, when we were old. This is the great historical evolution of medicine and what has favored the great progress in Alzheimer's disease.

"But being 75 years old today is not the same as 30 years ago, when we were old. This is the great historical evolution of medicine and what has favored the great progress in Alzheimer's disease"

--- When I started at the Vall de Hebrón Hospital, both in neurology where I was, and in traumatology and rehabilitation, when we had a person who had suffered a thrombosis or a cerebral hemorrhage, if they were over 65 years old, the rehabilitators understood that there was nothing to be done and we left them as chronically ill. Now, at 80 years old, we put in prostheses. My mother had a thrombosis at 88 years old, entered the stroke program, and then underwent rehabilitation to be able to stay on her feet. Her mind was clear, she played dominoes, watched movies, and was with her great-grandchildren. These are today's big scenarios.

--- Also in Alzheimer's.

--- Also. Now we are in the scenario where we will diagnose more and more in the prodromal state ---when a certain anomaly, discomfort, symptoms prior to the onset of the disease are detected---. And in addition to diagnosing them with the clinical study, we will also determine the phenotype and genotype, their characteristics, such as the specific memory failure focused on the hippocampus. We will have a guide to everything that leads to Alzheimer's. With medications like the one just approved in the United States, we have to make sure that there are detectable traces of Beta-amyloid in the brain and that the cognitive decline is mild. Right now, we can only confirm this by doing a lumbar puncture, which is common in the world of neurology, but which, in addition to being an invasive test, cannot be done on everyone. For now, only in this way can we locate beta and tau and know if the cutoff point of their accumulation is pathological or not. Only then can we treat with this new drug. The alternative to lumbar puncture is to look for a neuroimaging marker (Beta-amyloid PET) which is expensive for our health system, over 1,200 euros. If this protein is not perceived, even if they have cognitive impairment or mild dementia, the new medication cannot be administered because what the drug does is clean the Beta-amyloid, and if there is none, it will do nothing. This is the biggest restriction on the prescription of this drug.

--- Is research also being done for other phases?

--- And very much so. And this is the success in Alzheimer's disease, that with each small advance we will bring others to light. This drug approved in the United States, Lecanemab, now its commercial name is Lequembi, is the tip of the iceberg. It means two successes at once. First, having achieved clinical improvement in the disease, which does not mean curing. It means that, if my falling slope is 100%, now the slope has been reduced by 27%. It has made the decline less. It has reduced the danger of falling, by more than 25%. If the slope is gentler, in the treatment time, 18 months in the map of the mathematical formula, with 27% I can gain 5 or 6 months of life for these people. This is the clinical success.

--- And the other success?

--- The other advantage is that, once I have a drug on the market, people have more quality of life and survival. But it also ensures that other drugs under investigation can be adapted, learned from, modified, as has happened in oncology. One objective leads me to another. Even if only a survival of two or three months is gained, in this time I will learn what the most immediate effects are, and in the future, and thanks to these people, progress can be translated year after year. This has been the success of oncology and will be our success. We will understand that a treatment will not go alone, but that we will have to combine it with others, as will already be done now, but I will have other targets that will not be Beta-amyloid, which will cumulatively improve the patient. This is not science fiction, we already have this and we will improve it. By the end of 2024 or 2025 we may have two more drugs, and in the medium term, the more we know how Lequembi behaves in the real world, the more possibilities for improvement and better prospects we will have.

"The other advantage is that, once I have a drug on the market, people have more quality of life and survival"

--- No. Now they have it approved in the United States, but they have to negotiate prices, regulations, administrative part, and this autumn it can be prescribed or perhaps earlier, but the North American regulatory body does not govern the European one, which has its own medicine agency and which will also have to approve the new drug and everything that comes after it. A committee of experts will do it, which will validate it, allow it to enter the European market. Europe is somewhat more conservative and perhaps the machinery here goes slower, but counting on the approval of the FDA (Food and Drug Administration), it will only be necessary for European experts to analyze the results and say whether they are laudable or not. I think it will be fast. A good scenario would be for it to be approved in Europe by the end of this year. Afterwards, each State has its agency and regulatory process. With very good prospects, the drug could be part of public prescription in Spain in July of next year. We hope to have this gift next summer.

"With very good prospects, the drug could be part of public prescription in Spain in July of next year"

--- Well, approximately between 40% and 60% would be in this prodromal range or with mild dementia. But each case has to go through a funnel, that of Beta-amyloid biomarkers, and a lumbar puncture will have to be performed to properly refine this biological diagnosis of Alzheimer's disease. In ACE, this would represent between 10% and 15% of this group (that 40% to 60%).

--- Is any alternative to lumbar puncture also being studied to find biomarkers and make diagnoses more accessible to everyone?

--- Yes, for some time now, markers have been sought that tell us that we are facing Alzheimer's disease, which are TAU markers in a blood sample. These studies are already very advanced to achieve the approval of a peripheral biomarker for the disease, with a simple blood draw. It would be easier, much cheaper and repeatable, and this would greatly speed up the prescription of treatments and management of patients to be treated. Research has been going on for many years, perhaps in the very near future we could have it approved. Beta-amyloid cannot be found in the blood in very small quantities, but TAU is very easy to detect. And, if present, it correlates with the Beta-amyloid that is in the brain. We are seeing this in research, we relate cerebrospinal fluid and plasma results. At ACE, we have 1,500 cerebrospinal fluid samples related to 1,500 plasma samples to confirm their good correlation. These biological samples are enriched by their genetic study, neuroimaging, and phenotype. These studies are what will consolidate the use of peripheral markers, and we already have a lot of experience with them. It would be a success if the approval of these peripheral biomarkers were consolidated in a year, which would make our work much easier and where all the research in the world is focused.

--- ACE is a pioneering center that addresses all 360 degrees of the life of a person with dementia.

---That is our goal. We are a non-profit foundation, just as we envisioned it when we launched it, to accompany the Alzheimer's community and to give them, not dignity, which they already have, and no one has to give it to them, but to put ourselves at the service of their needs, to know them at all times, because they are changing. Our question is: What can we do for them? We currently have 24 active clinical trials and have conducted 152 since 1996. We have a collection of 19,400 genetic samples that we contribute to international studies that have a very important weight because they are very homogeneous, because they are from a single center with a protocol. This is a very valuable and necessary asset for international research because it is not so common to find such large collections with this homogeneity, precision, and the same way of storing data, this gives extraordinary value to our collection which is available to anyone who wants to investigate.

"We are a non-profit foundation to accompany the Alzheimer's community and to put ourselves at the service of their needs, not to give them dignity, which they already have, and no one has to give it to them"

--- Barcelona is an international hub in research. Here we have centers that have been working for a long time on plasma and cerebrospinal fluid biomarkers. This leadership of ours ---of ACE--- in the rigor of our genetic samples, (the collection is named GR@ACE) makes us an active member of international research groups where prestigious centers such as Mayo Clinic, the universities of Pittsburgh, South Texas, and Washington and international genetics groups such as the Cohortes for Heart and Aging Research in Genomic Epidemiology also participate. We are also part of the Alzheimer's Disease International, the world federation of associations dedicated to the disease, and the European Alzheimer Disease Consortium. In some international studies, we have contributed up to 40% of the genetic samples and we are present in any genetic study that is designed. The centers in Catalonia occupy the first places of excellence in the ranking of all Spain and also internationally in terms of publications. Right now, following the idea of the more the better and no one excluded, we have obtained an important grant from the Carlos III Institute to start talking about precision medicine, where genetics plays a relevant role, and biomarkers and artificial intelligence will be added. This program is led by the Reina Sofía, Pasqual Maragall foundations, the Hospital de Sant Pau and us. Working together we achieve notable results and position ourselves on the international stage and gaze.