The great revolution against Alzheimer's: "It's the first time in human history that we've managed to slow the disease."

The fight against Alzheimer's has entered a new era. The emergence of new drugs that slightly slow its progression and the discovery of biomarkers that pave the way to preempting the disease have revived hope for curbing a disease that affects 50 million people worldwide. After decades of failure, without finding effective treatments for a dementia that destroys memory and individual autonomy, the scientific community is looking forward to the diagnostic and pharmacological revolution they have at hand. A panel of experts published a series of articles in The Lancet this Monday, outlining the advances and also addressing the significant controversy surrounding the new treatments, the first to alter the course of the disease, but challenged for being expensive, having side effects , and having modest efficacy.

Juan Fortea, head of the Dementia Neurobiology group at the Sant Pau Research Institute and co-author of one of the articles in The Lancet series, says that Alzheimer's research is at a moment of "paradigm shift." "We are not curing the disease," he clarifies, "but it is the first time in human history that we have managed to slow the course of Alzheimer's." Responsible for this scientific turning point are a new generation of drugs that eliminate the beta-amyloid protein, which accumulates in diseased brains, and slow the progression of the disease. Albert Lleó, head of Neurology at Sant Pau in Barcelona, ​​​​asserts that this is only "the beginning of the journey": "There are 138 more drugs under research. These are the first of many to come." Science is also investigating, for example, the potential of semaglutide , which has already revolutionized the treatment of obesity.

The drugs that have raised hopes are called lecanemab and donanemab . In clinical trials, the former reduced disease progression by 27%, and the latter by 35%. Both are approved in the United States and other countries, but the more conservative European Medicines Agency (EMA) struggled to approve lecanemab (it did so a year ago after an initial rejection) and is still considering donanemab's approval.

Both drugs have been surrounded by controversy, including within the scientific community. First, due to their potential side effects—cerebral hemorrhages and the death of two patients , in the case of lecanemab, for example—but also due to the concerns raised by its clinical benefits: What does a 27% reduction in disease progression mean for a family's daily life? Other issues raised include its price (estimated at around €24,000 per year per patient) and the fact that it was only intended for very specific patients, in very early stages of the disease and with very specific characteristics.

In The Lancet series, the authors—some of whom have declared conflicts of interest due to relationships with the pharmaceutical companies that manufacture these drugs—analyze this "range of reactions" and the "skepticism" these drugs generated among the scientific community and ask whether the same would have occurred in other diseases. In fact, they even compare the efficacy, costs, and impact of the new Alzheimer's drugs with the same variables found in other biologic drugs for other conditions. For example, they point out: with lecanemab and donanemab, there were serious adverse effects in one in every 300 patients and one in every 65, respectively; but also in trials with pembrolizumab (an immunotherapy) for lung cancer, side effects occurred in 27% of cases. Another example they give: with anti-amyloid drugs, the reduction in disability in Alzheimer's is similar to that found in other trials with biologic drugs for rheumatoid arthritis or multiple sclerosis.

Based on the life history of other biologic drugs in other diseases, the authors argue that the magnitude of the effect could be very similar. In these cases, they argue, prices are also higher and are not free of side effects. Regarding limited access to a very specific group of patients—experts estimate that only 5% of people with Alzheimer's will benefit, for now—the authors point out that in multiple sclerosis, for example, the use of innovative drugs was limited to 36% in 2017 and rose to 74% in 2020.

"What these authors are putting forward isn't a direct comparison with other diseases, but rather a demonstration that there are other therapies in medicine that have a comparable magnitude of effect, but Alzheimer's has characteristics that undervalue the advances," says David Pérez, head of Neurology at the 12 de Octubre Hospital in Madrid, who was not involved in this series. The doctor refers to a handful of variables, including scientific misgivings and social prejudices, that have created a favorable environment for controversy.

Pérez says, for example, that the history of Alzheimer's drug development has been "bumpy," marked by successive failures that planted seeds of distrust in the scientific community. The controversy surrounding aducanemab , a drug approved with a shoehorn in the US but which flopped on the market and was later discontinued by the pharmaceutical company itself, didn't help either: "It was approved in a twisted way, without any clear benefit, and that created an environment of distrust," Pérez explains.

Nihilism and ageism in the controversy

There is also "a lot of nihilism" inherent in this disease, Lleó maintains: "Many times the diagnosis is not made accurately, and since there is no treatment, there is no need for the population to demand a diagnosis or the timescales required for stroke or cancer. Sometimes, the symptoms are considered part of normal aging. And all this gives the image of a disease for which there is little that can be done."

Another point that alters the debate, in Pérez's opinion, is ageism: "It's a disease that affects older people who cannot speak out and demand anything from society. These patients are a fragile group."

The magnitude of the disease, according to the experts consulted, has also fueled doubts wherever decisions are made. “If it weren't such a prevalent disease, if it didn't cause a strain on the healthcare system, on costs, and on process changes, some of the controversy wouldn't have arisen. If it were a rare disease, we have little doubt that this would have been approved without any controversy and very quickly,” Fortea says.

This first generation of drugs poses a challenge for healthcare systems. Both in identifying patients who may benefit—this requires diagnostic and biomarker testing to confirm the disease, as well as genetic studies to rule out incompatible mutations—and in the treatment and follow-up itself: the therapy is intravenous, administered in the day hospital, and requires follow-up MRIs to monitor possible bleeding. “It's one thing to see patients in outpatient clinics as they were before, once every six months or every year; and another thing is treatment with lecanemab, which involves infusions every 15 days in the day hospital, plus four MRIs a year with many visits… A patient goes from having one or two relatively short visits a year to having 24, 30, or 35 visits. Imagine the healthcare burden that entails. It's going to be hard for the system to adjust, but the fact that it's a minority of patients [at first] will allow the system to adapt,” Fortea argues.

The experts consulted indicate that the potential side effects are manageable, and regarding the clinical benefit, Fortea points out that "that 30% would translate into the patient gaining six months in 18 months." Or to put it another way: "To progress to the next phase, you progress 30% more slowly. You maintain greater autonomy and a higher quality of life because we are slowing down a disease that causes a lot of disability. We are not curing the disease. Patients are getting worse, but they are doing so more slowly," she adds. In an interview with EL PAÍS , Cristina Maragall, president of the Pasqual Maragall Foundation, argued that for both the scientific community and families, "it is essential that these medications begin to be used."

Diagnostic revolution

However, therapeutic advances are only one part of this scientific transformation that Alzheimer's is shaking. The other leg, diagnosis, is also making great strides. Above all, with the development of biomarkers that identify biological traces of the disease at an increasingly early age. The authors estimate that the arrival of plasma biomarkers, which detect traces of the disease in the blood—with a simple extraction, such as that performed in a conventional blood test, biochemical signs of the disease can be identified—"will lead to a new diagnostic revolution."

These tools are "crucial" to confirm the diagnosis at all stages of the disease, Fortea asserts. The doctor explains that when the clinical evaluation and neuropsychological examination confirm mild cognitive impairment, in 60% of cases it will be Alzheimer's, but in the other 40% it will not; and depending on the situation, the patient's progression and prognosis will be very different. "Therefore, I absolutely need a biomarker to identify who has Alzheimer's. Otherwise, I won't know what's happening," he asserts. In asymptomatic settings, on the other hand, the only way to select people with Alzheimer's will also be the biomarker, he asserts. "The day there are preventive treatments, that biomarker will be our only tool to identify these people," he adds.

The doctor is very optimistic about the medium term: “We can now diagnose the presence of proteins [related to Alzheimer's] in the brain of cognitively healthy people. We still can't predict with certainty whether or when all of these people who have these proteins in their brains will develop the disease, and that's why population screening isn't recommended, but this isn't science fiction. These are clinical trials that are underway and will be published in 2027. In two years, we'll know if removing amyloid in people without symptoms slows the onset of the disease.”

If this is the case, he specifies, "it would be justified to conduct population screenings and try to prevent it." "We're not there yet, but we have diagnostic tools that work and clinical trials are underway. This doesn't end with these two approved drugs; there are many more to come, not only in these stages of the disease but in others as well. The disease in five years may be unrecognizable from the perspective of how we treat it, prevent it, and what we do."

Experts also predict a boost in the field of prevention. In fact, a scientific review identified 14 risk factors (tobacco, hypertension, sedentary lifestyle, and pollution, among others) that should be avoided to avoid almost half of dementia cases. "There is potential in prevention," argues Eider Arenaza-Urquijo, ISGlobal researcher and author of one of the articles in The Lancet series: "We have already seen a study that has shown that a lifestyle intervention—physical exercise, nutrition, cognitive and social activity—has an impact on cognitive decline in people at higher risk of developing Alzheimer's," she exemplifies.