Alzheimer’s is a complex disease that begins many years before symptoms appear. The pathological aspects on which we try to intervene are more than one: they range from trying to counteract the accumulation of plaques of the beta amyloid protein and the hyperphosphorylation of the tau protein, which forms neurobrillary clusters responsible for neurodegeneration, to trying to reduce inflammation and oxidative stress. Thinking of attacking just one of these key factors is at least presumptuous: “As happens in other specialties, from oncology to internal medicine, the way to go is that of combining therapeutic strategies and adopting a personalized approach” he says. Alessandro Padovani, of the University of Brescia and director of the Neurological Clinic of the Spedali Civili. “It is necessary to have the courage and also the economic strength to conduct long clinical studies, stratifying patients according to their condition and stage of disease, to have biological efficacy indicators that justify the continuation of the study and to add more treatments in combination” .
Alzheimer’s, what is the point of studies to know if you will get sick
at Federico Mereta
Alzheimer’s disease will be discussed at the XXV World Congress of Neurology organized from 3 to 7 October by the World Federation with the Italian Society of Neurology SIN, which should have been held in Rome, but will take place in virtual mode. Padovani will talk about a topic wrongly considered minor: symptomatic drugs.
“The combination of different drugs can give more favorable results than what is commonly believed today. Furthermore, the symptomatic ones are not palliative, but actually have a protective action and reduce some indicators of progression such as hospitalization and need for assistance “explains Padovani, recalling, for example, the dopaminergic system at the basis of extrapyramidal motor control whose involvement is now widely recognized also in Alzheimer’s:” 35% of patients have extrapyramidal problems: attacking them allows to reduce motor symptoms and cognitive “. Neurostimulation, which appears to provide improvements in the patient’s attention and concentration that persist up to a few months after treatment, may also help.
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Pharmacological research is moving in many directions and, starting from the fact that people with type 2 diabetes are more at risk of developing Alzheimer’s and other epidemiological data, it has come to the discovery of possible common pathophysiological mechanisms between insulin resistance and Alzheimer’s. We therefore focused on the study of the effects of antidiabetic drugs, in particular the analogues of human GPL-1 liraglutide and semaglutide, on the accumulation of beta amyloid and phosphorylated tau and also on brain function and cognition. In vivo studies in mouse models of Alzheimer’s, but also of Parkinson’s, have shown neuroprotective and neurotrophic effects of these molecules, benefits mediated by the improvement of insulin signaling in the brain. But the passage to humans, so far, has not given the promised results: in the British phase 2 study Elad, which started in 2014 at Imperial College with liraglutide, the Pet FDG, a method for assessing glucose metabolism in the brain, did not has detected changes. Now, let’s try the other similar molecule, semaglutide.
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An international study, funded by the manufacturer, is also underway in Italy with the recruitment of patients with mild disease. “On patients with type 2 diabetes, administration for two years is effective in reducing the incidence of cognitive impairment” explains Alessandro Padovani who, however, recalls the importance of “investing in drugs potentially capable of acting in the most advanced phases and therefore in patients who already have dementia to reduce disease progression “. Working on drugs like these, alternatives to anti-amyloids, is also important “in the light of the perplexity of some of the scientific community on the viability of the path of monoclonal antibodies”.
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Amyloid beta protein
In fact, great hopes, partly unfulfilled, have been placed in immunotherapy for the treatment of Alzheimer’s. There are two approaches: on the one hand, the administration of a protein similar to the offending one, beta amyloid, to stimulate an immune system response and, on the other hand, the so-called passive immunization which consists in the injection of monoclonal antibodies that bind the protein to remove it with the so-called clearance process, or disposal. Last June, the Food and Drug Administration FDA approved the first of these antibodies, aducanumab, which reduces brain amyloid burden, but whose clinical benefit remains to be demonstrated. This has raised many discussions, in particular whether biological efficacy is sufficient for the approval of a drug, which in this case is however bound to the execution of other studies and the achievement of evidence of a clear and quantifiable clinical benefit, such as slowing the disease or reducing symptoms.
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“Active immunization is a long competition, aducanumab is the first but soon there will be others” says Padovani, recalling the side effects of immunotherapy. “Monoclonal antibodies must be better defined in their objective and among all the amyloid species, those that will eventually be identified as the most toxic or attackable must be selected”.
The side effects
Yes, because targeting as monoclonal antibodies selectively to the aggregated forms of Aβ is not an action without adverse consequences for the patient, because they trigger an important cerebral inflammatory reaction. In fact, the side effects are the subject of an FDA warning and have been studied in patients enrolled in the pivotal studies. “About 40% of the subjects develop amyloid-related imaging abnormalities, also called Aria (from the English amyloid-related imaging abnormalities)” explains Fabrizio Piazza of the School of Medicine of the University of Milano-Bicocca. Furthermore, recently, by comparing the health status of Alzheimer’s patients with the eligibility criteria for studies, it emerged that adverse events could be much more frequent in the real world.
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A natural model of adverse events
With his group, Piazza has just posted on Neurology a work, funded by the American Alzheimer’s Association and the Cariplo Foundation, which describes for the first time a rare condition, inflammation related to cerebral amyloid angiopathy, which is a natural model of ARIA, the adverse events observed in clinical trials. Knowing and knowing how to manage this disease, therefore, becomes even more important today, precisely because of its similarity to the inflammation triggered by the drug, the Aria, whose symptoms are edema and cerebral micro-bleeding. The team has also identified the management of these events: “For the first time, we show that it is necessary to intervene immediately with cortisone” explains Piazza “whose effectiveness is also clear in preventing relapses”.
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As to what you trigger these dangerous events, both spontaneous and those due to the treatment of monoclonal antibodies, there are still no certainties. “Already in 2013 we saw that in patients with cerebral amyloid angiopathy there is an increase of autoantibodies against beta amyloid in the cerebrospinal fluid which, coincidentally, are just similar to those administered against Alzheimer’s” explains the pharmaceutical biotechnologist who, already ten years ago, he founded iCAβ International Network, a consortium of 25 centers in 13 countries for the identification and validation of biomarkers of inflammatory amyloid angiopathy and Alzheimer’s disease. They are therefore the main suspects. “The massive presence of circulating beta amyloid certainly plays a role in both types of ARIA. Parenchymal and vascular deposition is probably important, but the patient’s prognosis is not governed by such amyloid deposition but rather by inflammation” explains Piazza, to work precisely on the cells of the microglia to try to understand these inflammatory phenomena to suppress them. “Identifying specific markers would be very useful for the differential diagnosis, now it is impossible to distinguish the two ARIAs”, the spontaneous ones, due to amyloid angiopathy, from those caused by the treatment.
Alzheimer’s, what is the point of studies to know if you will get sick
at Federico Mereta
Complicating matters, in fact, is the fact that most patients diagnosed with Alzheimer’s have concomitant amyloid angiopathy of some degree. For them, therefore, the therapy could be risky. And yet, these patients, who in 50% of cases evolve into Alzheimer’s, “would be the best candidates for treatment, in view of the precocity and timeliness of intervention”, comments the researcher. Research is therefore crucial for its implications in anti amyloid drugs: to arrive at clear indications on who to treat, who to exclude from treatment and how to manage adverse events. This is an emblematic example of how the study of rare diseases can have wide-ranging repercussions and Alzheimer’s is not just a problem for neurologists. Collaboration and translationality are necessary conditions in the fight against Alzheimer’s.
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