Studies, research and promising new frontiers on Alzheimer’sfrom tests for early diagnosis to therapies that aim to slow cognitive decline. On the neurodegenerative disease – which affects approximately 5% of people over 60 and in Italy there are an estimated 500 thousand patients (ISS data) – it is a flourishing of scientific activity driven not only by social and health needs, but also by gigantic commercial interests. But all that glitters is gold, we are in the presence of concrete data or dazzled by the mirage of a cure definitive?
“There is no mirage because we are all aware that the goal of a cure in the true sense of the word is still far awaybut it is true that compared to a few years ago, a great interest is being reawakened in the early diagnosis and treatment of Alzheimer’s – with this term we want to include all dementias, even if Alzheimer’s is the most frequent form, but not the only one – because it is a ‘dish’ that has as a side dish an impressive organizational and economic fallout”. Paolo Maria Rossini, head of the Department of Neuroscience at the IRCCS San Raffaele in Rome, took stock with Adnkronos Salute.
Every week, scientific journals publish studies on new “diagnostic tests”. who would like to discover the disease before the symptoms appear and who say that having a biomarker (an instrumental diagnostic test) is ‘very cool’, that is, very accurate. The goal – warns the neurologist – without taking anything away from the scientific importance of these studies is not only to make an early diagnosis, but also to market in the most profitable channels (for example all pharmacies) a kit that potentially has hundreds of millions of buyers worldwide, considering all those over 50. There is great fervor on Alzheimer’s and research is very vital (in the last 3 years alone, 3 monoclonal antibodies have been approved by the American FDA, two of which, however, have not been approved in Europe because they are not very effective, very expensive and have several, even alarming, side effects”.
According to Rossini, “we should from now on act as was done for the Covid vaccine in which everyone – public opinion, political and health authorities of all countries – began to put pressure on the pharmaceutical industry (‘Big Pharma’) to put aside the goals of individual companies and unite all energies on this front to achieve a tangible result of treatment in the shortest time possible”.
On early diagnosis tests, be careful how we handle false negatives, there is an ethical question
“Most of the scientific works that have been published recently aim to identify a biomarker for example a blood test, a neuroimaging test, a genetic test, an electroencephalogram – explains neurologist Rossini – able to give us a biological diagnosis of the presence of agents that cause neurodegeneration underlying the various forms of dementia, before the symptoms appear. Very well, but all these biomarkers for various reasons – economic or time – have been tested on a population of elderly people at risk of developing an intermediate state of disease that ranges from normal brain aging to dementia. A population defined as ‘Mild Cognitive Impairment (MCI) which notoriously has a risk at least 10 times higher than elderly people of the same age and which in half of the cases after 3 years of ‘follow up’ develops the disease”.
“In summary, at the time of diagnosis of MCI, approximately half of the cases will already be in an initial prodromal form of dementia that will become clinically evident over the following 3 years, but the others will never have the disease; the reason why they do not get sick is not known – he warns – but it can be explained in summary by the presence of resilience factors that allow the brain to resist the attack of neurodegenerative factors. On this high-risk population (MCI) we are carrying out many studies that tested diagnostic tests to find a biomarker of Alzheimer’s in the blood (including the Italian project ‘Interceptor’, at the forefront in the world in this sector). However, this scenario is made confusing and a little disturbing by the fact that if one or more biomarkers are found in a person (let’s call him XY) it will be possible to say that XY has a biological diagnosis of neurodegenerative disease; however, it is known that up to 30% of those who have signs of biological disease will never develop (if followed over time) the clinical symptoms of the same disease; therefore, they will never become demented. Therefore – observes Rossini – XY is positive for the biomarker but if I follow him over time it will happen that he will not get sick, but in the meantime his life is destroyed from every point of view, especially if relatively young, because with the test he was told that he will become demented. Who will trust him anymore? Who will allow him to make a career? Who will trust his projects and his assessments?”
“Here it is based on these issues there is a big debate about these predictive tests (blood or other); is it enough to have the biomarker to say that you will have Alzheimer’s? Personally – suggests Professor Rossini – I will rejoice when some researcher demonstrates a serious biomarker (or a set of biomarkers sustainable in terms of costs, healthcare organization, non-invasiveness and widely available to all) capable of correctly predicting in 99.9% of cases those who will get sick compared to the false positives that today are too high with the biomarkers currently available. It would also be necessary to investigate much more into the resilience factors that allow those who have the altered biomarker not to get sick. Alzheimer’s and other dementias are diseases that work in the dark for years or decades before the symptoms become evident in a continuous ‘ping-pong’ between risk factors and resilience factors. If resistance factors were studied in depth, new therapeutic avenues could probably be found that enhance these biological factors that are present but are not sufficiently expressed in those who become ill.”
Several monoclonal antibodies approved in the US but not in the EU
Returning to the available drugs“the American agency for the drug (Fda) has given the ok to three monoclonal antibodies – Aducanumab, Lecanemab, Donanemab – all three ‘smart missiles’ that bind to and destroy the deposits of beta-amyloid. As mentioned, the European agency (EMA) has not approved the first two (Aducanumab and Lecanumab) because the biological efficacy is there but it is modest. The deposition of beta-amyloid disappears but the disease progresses anyway, let’s say that the biological and clinical aspect do not go hand in hand in analogy with what was described above). Furthermore – adds Rossini – these therapies are very expensive, they cost tens of thousands of euros. They are administered intravenously and therefore require an administration that involves hospital facilities. Every two-three months an MRI must be done to see if there are side effects, such as edema or microhemorrhages and if there are, the therapy must be interrupted. However, there are other drugs being tested, some of which subcutaneous or oral infusion, which act in part on the deposition of beta-amyloid and Tau protein and other agents supposed ‘killers’ of neurodegeneration. We are in Phase III of experimentation and this year researchers will open their ‘secret chests’ and we will know the efficacy and side effects of these therapies”.
If a way to reduce the impact of Alzheimer’s is found, could there be a cure for everyone? “On the treatment front, there is certainly a problem linked to the very high costs of these drugs and there, health systems need to equip themselves with a tool to select people at high risk. The ‘Interceptor’ project – the neurologist recalls – which ended recently and of which we are processing the data, goes in this direction. And Italy will be the first country in the world to be able to equip itself with an organizational model developed in 19 centers from Piedmont to Sicily. ‘Interceptor’ aims to develop a panel of biomarkers that are sustainable in terms of costs and health organization that – together with neuropsychological tests – will allow for the early diagnosis of Alzheimer’s disease. Furthermore, we will say what is the most effective combination of biomarkers to immediately distinguish elderly people who are in fact already ill (even if in a very mild form) from those who will never be ill”.
Finally, Professor Rossini clarifies how one of the principles that should guide research in the field of dementia is that of ” extend the period of autonomy of patients because that is what families ask for”. Stopping the evolution of the disease “by blocking it at the initial stages, when patients maintain almost all the autonomy of daily life, means alleviating the emotional/social/economic burden that today – for the most advanced forms of the disease – weighs almost exclusively on family members and caregivers”, concludes Rossini.
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