Debate on Drugs and Alzheimer's

The recent publication of a Cochrane review on anti-amyloid drugs for Alzheimer's has sparked a debate that some specialists find questionable. Cochrane reviews are compilations of scientific evidence widely recognized in the scientific community. The analysis, coordinated by Francesco Nonino, a neurologist at the Institute of Neurological Sciences of Bologna, examined 17 clinical trials involving 20,342 participants and concluded that these medications "probably do not reduce the severity of dementia" in a clinically significant way.

Although the drugs do eliminate the beta-amyloid protein from the brain, the purpose for which they were designed, this reduction does not translate, according to the authors, into a noticeable clinical benefit for the patients. The review also points to an increased risk of brain inflammation and cerebral hemorrhage, effects detected in imaging tests and whose long-term relevance remains unclear.

The conclusion has been replicated in the media. However, part of the specialized community has quickly questioned its conclusions and pointed out what they consider a fundamental methodological trap. Félix Viñuela, coordinator of the Cognitive Impairment Unit at the University Hospital Virgen Macarena in Seville, who has participated in some of the trials of these drugs, is one of the specialists questioning the approach. His objection is significant. The meta-analysis groups drugs that, although they belong to the family of anti-amyloid monoclonal antibodies, target different molecular targets within a very large and complex protein.

“The amyloid protein has many peptides. One molecule may go to the fibril, another to the protofibril, another to the larger aggregates. That one antibody has not been effective does not mean that another, designed for a different part of that protein, won't be either,” he explains. The practical effect of mixing them all is, in his opinion, “artificially diminishing the efficacy of those that have proven to work.” The analogy proposed by Viñuela is straightforward: in his view, it's like concluding that antihypertensives are ineffective by mixing in a single analysis the compounds that were approved with all those that failed in trials and never reached the market.

At the center of the debate are the only two anti-amyloid drugs with positive results in their own clinical trials: lecanemab and donanemab. Both have managed to reduce the progression of cognitive deterioration by 27% to 28%, which in practical terms means gaining between three to five years against the disease. They are not curative, but they are the first to demonstrate that Alzheimer's—considered irreversible since Alois Alzheimer described it in 1906—can be slowed in its progression.

Moreover, Viñuela rejects that the efficacy criteria of those trials are purely biological. “The primary parameters are not the reduction of amyloid; that is a secondary criterion. What was measured was the clinical impact on cognition and the quality of life of the patients,” he points out. And he adds a difficult argument to ignore: both the European Medicines Agency (EMA) and the FDA approved these drugs after evaluating precisely whether their effects were clinically relevant.

“A regulatory agency does not approve a drug for eliminating a protein if it does not have a real impact on the patient. There has to be biological plausibility, but with clinical impact,” emphasizes Viñuela, who is also the coordinator of the Cognitive Impairment Group of the Andalusian Society of Neurology.

He also emphasizes that “to say that the clinical impact on quality of life is irrelevant is to ignore the very essence of a clinical trial in Alzheimer's disease, where precisely the clinical impact, which we call the primary efficacy criteria, is evaluated”.

Funding and health system

On the other hand, the specialist does not shy away from issues related to healthcare funding. He acknowledges that the efficacy of these treatments opens a legitimate pharmacoeconomic debate—still pending in Spain, where the drugs are not funded by the public health system, unlike other European countries—about whether the benefit justifies their high cost and the complex healthcare infrastructure they require. He also recognizes that real-life evidence will be crucial to confirm or refine their results.

But drawing a line between “partial efficacy” and “nonexistent impact” is, for Viñuela, a leap that the data does not support. “This is not the end of the movie, but the beginning,” he concludes. “The fight against neurodegenerative diseases has just started, and discrediting the first real progress we have had in more than a century does not help to win it,” asserts the specialist.