Juan Fortea and Luis Gandía, researchers: "In Alzheimer's, we must move toward personalized medicine, as in oncology."

Alzheimer's research is going through a transformative moment. For the first time, drugs—the monoclonal antibodies lecanemab and donanemab—can be used to slow cognitive decline in its early stages, although their efficacy, adverse effects, and high cost continue to generate intense debate . The controversial lecanemab has been approved for marketing in Europe since April, and on July 25, the European Medicines Agency (EMA) also recommended approving donanemab, after re-evaluating its initial rejection.

Once this key hurdle has been overcome, final approval, or not, from the European Commission should arrive in the coming months. At the same time, advances in biomarkers, genetics, and early diagnosis are paving the way for more personalized medicine. According to the WHO, more than 57 million people worldwide live with dementia, and up to 70% of cases correspond to this disease. In Spain, it affects approximately 800,000 people.

At the end of the course Alzheimer's: A Pathogenic and Therapeutic Enigma on the Way to a Solution? , held from July 14 to 18 in Santander, as part of the Menéndez Pelayo International University (UIMP) summer program, and before the EMA's latest decision on donanemab was known, EL PAÍS spoke with its two coordinators: Juan Fortea (Salamanca, 46), a neurologist and director of the Memory Unit at the Hospital de la Santa Creu i Sant Pau in Barcelona, an expert in dementia and the relationship between Alzheimer's and Down syndrome; and Luis Gandía (Elda, 62), a professor of Pharmacology at the Autonomous University of Madrid and a leading researcher in altered neuronal communication mechanisms in neurodegenerative diseases. From clinical research and basic laboratory science, respectively, both analyze the advances, challenges, and unanswered questions surrounding one of the great healthcare challenges of the 21st century.

Question: What do we know today about the causes of Alzheimer's?

Juan Fortea. The ultimate cause of sporadic Alzheimer's remains unknown, as is the case with many other diseases. We should stop treating Alzheimer's as something exceptional. In genetic forms—such as autosomal dominant forms or Down syndrome—excess cerebral amyloid triggers a cascade that leads to neurodegeneration. Although there are no clear mutations in sporadic Alzheimer's, the biomarkers, natural history, and mechanisms are very similar, reinforcing the central role of amyloid. Despite criticism of this hypothesis, the positive results of the new anti-amyloid treatments—lecanemab and donanemab—support it.

Q. What links Down syndrome to Alzheimer's?

JF. Chromosome 21, tripled in Down syndrome, contains the APP gene, which produces the amyloid precursor protein. Having three copies of this gene is enough to develop Alzheimer's, making it clear that excess amyloid can trigger the disease. Clinical trials with anti-amyloid therapies for people with Down syndrome will begin this year in the US, raising hopes of modifying this risk.

Luis Gandía. Furthermore, this population is highly predictable in terms of the age at which the disease begins. However, they continue to be unfairly excluded from many clinical trials, despite the fact that, unfortunately, they are an excellent model for studying the disease.

Q. Chronic inflammation is linked to many diseases . What role does it play in this?

JF: It's fundamental. As early as 1906, psychiatrist Alois Alzheimer described activation of glia (the tissue that supports neurons) in the brain of Auguste Deter, the first patient diagnosed, that is, brain inflammation, along with amyloid plaques. Today, we know of many genes involved in the inflammatory response associated with the disease. Efficient microglia (the brain's immune cells) can contain the damage, but if they fail, the disease progresses. Furthermore, we will soon know whether GLP-1 analogues, drugs used for diabetes and obesity (such as Ozempic), are also neuroprotective.

LG. Neuroinflammation is central to basic research, but it doesn't act alone; it interacts with multiple pathological pathways. It's key to maintain an integrative view of the neurodegenerative process because it's the combination of multiple factors that causes disease.

Q. What is the relationship between diabetes and Alzheimer's?

JF. Alzheimer's disease involves significant metabolic alterations: patients lose weight up to 10 years before symptoms appear—it's a non-cognitive manifestation of the disease—and present early cerebral hypometabolism and poor glucose utilization. Furthermore, amyloid and insulin share a degrading enzyme. For all these reasons, some researchers call it "type 3 diabetes."

LG. Neurons in Alzheimer's respond poorly to insulin, which reinforces this idea. Still, it's key to remember that, although diabetes can make it worse, without beta-amyloid, there's no Alzheimer's.

Q. There are also known links to certain infections . What do we know about this relationship?

JF. So-called chronic low-grade inflammation can worsen many diseases, such as cardiovascular or brain diseases, where it overwhelms microglia , the immune cells already trying to deal with amyloid. A good example is periodontitis, a gum infection that many people underestimate , even though the area affected can be equivalent to having a wound the size of the palm of your hand. There are also minority theories about infections as a direct cause; for example, syphilis or the herpes virus . We shouldn't rule them out if they open up therapeutic avenues.

LG. Decades ago, attempts were made to treat inflammation with traditional anti-inflammatory drugs (NSAIDs), without success. Today, the focus is on neuroinflammation, with more targeted approaches. We're returning to old ideas, but with better tools.

JF. Those attempts were naive: some of those drugs didn't reach the brain well, and we didn't have biomarkers. Today, with PET [brain alterations visible through imaging techniques] and blood biomarkers, we're starting to get some keys right. Like when you play a piano by ear and can't quite get the melody, but something sounds. For example, a trial with a microglial target (TREM2) failed due to adverse effects (cerebral edema), but it showed that we can intervene in key mechanisms, such as amyloid. And that gives me hope; we're already starting to see results...

LG. ...And that tapping of keys will soon seem like a melody. After 20 years of drought, a paradigm shift is beginning.

JF: Before, my response to patients was usually: "There's nothing new." But now, thanks to years of investment, there are tangible advances. Blood biomarkers, which cost around 50 euros, can revolutionize diagnosis. I hope that in three or four years we'll go from 10-20% of diagnoses with biomarkers to 80-90%.

Q. Can they be used in the general population?

JF: In patients with symptoms, having a biomarker that confirms or rules out Alzheimer's is essential. But screening is still not recommended in the general population. The reason? We still don't have an effective preventive treatment. Without clear intervention and accurate communication of individual risk, generating uncertainty would be irresponsible. However, this could change in two or three years if we improve on both fronts: the ability to stratify risk and the availability of effective therapies in very early stages.

Q. What are the implications of recent proteomic profiling studies funded by the Gates Foundation ?

JF: They are a complementary approach to current biomarkers. Instead of searching for two or three specific biomarkers involved in the disease, proteomics analyzes thousands of proteins simultaneously to detect patterns associated with different diseases. This can not only improve diagnosis but also reveal common mechanisms between pathologies. It is plausible that in the future there will be drugs targeting biological pathways shared by Parkinson's and Alzheimer's.

Q. Where are we in terms of treatments?

JF. In addition to lecanemab and donanemab [already recommended by the EMA], the results of trials with GLP-1 analogues, a different pathway linked to metabolism, will be announced in November. This means that in the coming years, we could have several drugs with clinical efficacy and capable of clearly modifying the biology of the disease, according to biomarkers.

LG. And it's precisely biomarkers that will allow us to better select the patients who can truly benefit. Not everyone responds equally; we need to fine-tune things.

JF. Exactly. That's why we insist on its key role. As in oncology, in Alzheimer's we must move toward personalized medicine. Although all patients have amyloid, not all cases are the same. Anti-amyloid therapies probably won't work in advanced stages, but they are already being tested in preclinical stages. If they prove effective there, we could go from treating Alzheimer's to preventing it. That would truly be a revolution.

Q. The British NICE—the agency that decides which therapies the public system funds and serves as a reference for its European counterparts—has decided not to fund either lecanemab or donanemab. It argues that their clinical benefit is modest, and that administering them through intravenous infusions, along with periodic MRI monitoring due to the risk of cerebral edema, represents an excessive cost. What is your assessment?

JF: I'd like to be very clear. First, let's put this in context: just as the EMA did in Europe with lecanemab [and just did with donanemab], regulatory agencies in the US (FDA), Japan, South Korea, China, and the United Kingdom have approved these drugs. That is, they have concluded that the risk-benefit balance is favorable. What NICE has done is different: it recognizes their efficacy, but does not fund them because the benefit obtained does not justify the cost. However, Medicare and Medicaid in the US already cover 80% of the cost, as do public systems in Japan and China. Other European funding agencies have not yet commented.

Furthermore, NICE has attributed the cost of treatment to resources that should already be available, such as biomarkers, neuropsychological assessments, and specialized units. It's like arguing that a drug can't be prescribed because hospitals would have to be built; it makes no sense. These infrastructures are necessary anyway and shouldn't be included in the price of the medication.

LG. We also face that risk in Spain: that the EMA approves them, but then they aren't funded here. We need to make policymakers understand that what seems expensive today will be offset in a few years by the direct and indirect costs we'll save.

JF: Exactly. And it would be a tragedy if they weren't funded. These drugs are targeted at a very specific phase of the disease, when the first memory lapses appear, and even then, only between 5% and 15% of those patients will meet the criteria to receive them. But the impact will go much further: it will improve early diagnosis, care pathways, access to biomarkers... It's an investment in the entire system.

Q. During the UIMP course, you talked about “integrative therapy” for Alzheimer's. What do you mean?

LG. This was explained by neurologist Mercedes Boada. It involves offering comprehensive care that combines psychological support, cognitive stimulation , physical exercise, and socialization. A good example is some day centers that don't operate as simple "parking lots" but instead offer personalized programs to keep patients active and slow their deterioration. Unfortunately, this ideal model is still very rare. In many nursing homes or private centers, care is limited to support, but without real stimulation, which is key to preserving function.

JF. Alzheimer's is probably the most unequal serious disease in our healthcare system. The patient journey—who diagnoses them, what tests they undergo, whether or not they access biomarkers—varies even within a single city, depending on the center or professional treating them. We need a well-resourced national plan that guarantees quality and equity across all care.

Q. What can we do as a general population to reduce the risk of Alzheimer's or other dementias?

JF. Leading a healthy lifestyle is key. There is very solid evidence—such as that collected by The Lancet dementia commission —that many cases could be prevented with better education, a balanced diet , regular physical activity, control of cardiovascular risk factors, and avoiding social isolation. It's also essential to be alert to early symptoms and see a doctor early. I also encourage participation in research. Today's treatments exist thanks to those who collaborated in clinical trials.

LG. Maintaining an active social life also protects the brain. Isolation, spending the day alone in front of the television, is very harmful. There are very illustrative examples in Japanese villages where daily interaction with neighbors helped delay cognitive decline.

Q. What would you say to someone who has just been diagnosed with Alzheimer's?

JF: It's a serious diagnosis, but they shouldn't lose hope. The disease usually progresses slowly, and many people maintain a good quality of life for years. Many patients aren't even fully aware of their deterioration, which is known as anosognosia; and this, although it may seem paradoxical, can alleviate some of the family's suffering. Furthermore, there are increasing reasons for optimism thanks to scientific advances.

LG. The patient shouldn't be hidden or isolated. On the contrary, keeping them active and socially engaged clearly improves their well-being. A suitable day center with stimulation programs can be much more beneficial than caring for the patient at home without such support. And it's important to remember that, in many cases, Alzheimer's can be lived with for many years without it being the direct cause of death.