The search for an effective treatment for Alzheimer’s disease has not yet reached a turning point. In fact, the results from the Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) Colombia Trial study are not positive. The investigational drug crenezumab did not slow or prevent cognitive decline in people genetically predisposed to developing the disease. But this is not a setback to Alzheimer’s research. Nor of the end of the hypothesis of beta-amyloid as the engine of the disease.
Hit the beta-amyloid
Crenezumab is an investigational drug, technically a monoclonal antibody directed against the oligomers of beta-amyloid, the protein that makes up the plaques of the same name, believed to be one of the causes of the disease. In fact, beta-amyloid plaques accumulate in the brain, damaging neurons. Crenezumab is not the only drug developed to target beta-amyloid: even aducanumab, the only (and controversial) drug approved (in the US) for the treatment of Alzheimer’s disease, has the same target, but not the only one. But if on paper the accumulations of beta-amyloid seem to be an ideal target to hit in order to combat the disease, the experimental evidence on the effectiveness of this approach has been conflicting. Aducanumab itself, for example, has been shown to actually reduce beta-amyloid, but this hasn’t translated into cognitive clinical benefits, not always. The absence of this evidence of efficacy, even admitting a plausible rationale, and the methods of approval in spite of the data, have been at the center of the controversies that have arisen around the approval of the drug, rejected for now by the European Agency for medicines.
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The study in people at risk
The study on crenezumab, carried out with the support of the National Institute on Aging (Nia), the Banner Alzheimer’s Foundation and Roche, involved a population of young subjects with a high genetic risk of developing the disease (and for this reason called hereditary or familial form Alzheimer’s). In fact, the participants were people with gene mutations who would most likely have developed the disease, well before the onset of dementia in its sporadic forms, usually already between 30 and 60 years of age. In particular, in this case there were over 200 people – belonging to the largest family with familial Alzheimer’s in the world, the relatives of Antioquia – two thirds of whom with the PSEN1 E280A mutation, one of the responsible for the high risk of disease in these hereditary forms. . Participants were randomized: those with the mutation received the drug (in increasing doses over the course of the study), others placebo, also given to a mutation-free group. The involved group had no cognitive problems or symptoms of disease at the start of the study, and the administration of the treatments lasted for at least 260 months. At the end of the study, when comparing the groups of participants, the researchers observed no statistically significant differences in terms of cognitive ability or episodic memory function. Time to give up the search for a beta-amyloid drug?
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Why drugs don’t work
No, second Alessandro Padovani, director of the neurological clinic of the University of Brescia: “All the experimental models and some clinical evidence indicate that beta-amyloid plays a role in the disease, and we cannot think about fighting Alzheimer’s today if it is not also treated amyloidosis “. Also, and not only: one of the reasons why drugs that target beta-amyloid struggle to bring results is that probably in the fight against Alzheimer’s it is necessary to act on several fronts, considering the multifactorial nature of the disease. But not only: referring to the particular case of the data coming from the crenezumab study, perhaps the timing may have been too tight. If on the one hand, in the past, it has often been talked about the difficulty of observing results in phases considered too advanced in the disease, acting too soon could be a problem: “When we enter such early areas of intervention, it is necessary to find ways of evaluating more sensitive than those used or take into account longer time windows to evaluate the results ”, continues the expert. Although long – from 5 to 8 years – they were those foreseen in the study for the evaluation of the clinical effects of the treatment. And this is why it is too early to think of abandoning the beta-amyloid hypothesis: “It is a difficult road, but some evidence accumulated with antibodies capable of effectively reducing beta-amyloid and inducing clinical effects make it difficult today abandon it: the results that will come from other studies in progress on other molecules, from those on the same aducanumab, such as gantenerumab, lecanemab and donanemab will help to clarify “. But even detailed data on the crenezumab study itself – from imaging, cognitive, to molecular biomarkers – could help drive research in the field, NIA said.
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Meanwhile, according to Padovani, some considerations should also be made: “The disease is more complex than we thought, and we still have to clarify its underlying mechanisms. For example, so far we have mainly focused on fighting the beta-amyloid portion present in the extracellular compartments, but it could also be very important to consider the intracellular potion – he continues – it is not entirely clear whether the one outside or inside the cell is more toxic. “. Finally, one of the problems related to the failures, or rather the negative results of the studies against beta-amyloid is the crux of the specificity and bioavailability of monoclonal antibodies: “They may not be so specific against the more toxic forms or there may not be enough of them”, concludes the expert.