2023-09-16 09:56:14
The hopes were huge, the disappointment was even greater: When two studies testing an Alzheimer’s drug were stopped in 2019 due to a lack of prospect of success, the frustration in the experts was clearly noticeable: “A disaster for the entire field,” one complained expert, another spoke of a “big disappointment for neuroscience.”
Four years later, there is a sense of optimism again: On the one hand, the antibody aducanumab, whose testing had been stopped at the time due to a lack of prospect of success, was approved for Alzheimer’s therapy in the USA in 2021 – in an extremely controversial decision. Secondly, the antibody Lecanemab came onto the market in the USA at the beginning of 2023 – the approval of which is currently being examined in the EU. And recently the journal “JAMA” published results of a study for a third antibody, Donanemab, which is pending approval in the USA. The antibodies are intended to cause certain deposits to be broken down in the brain.
The media judges the development as a “breakthrough” and speaks of a “milestone” and a “turning point”. The Judgment by many experts is more sober: “The benefit of the antibodies is currently still manageable,” says Richard Dodel from the University of Duisburg-Essen, Alzheimer’s expert at the German Society for Neurology (DGN).
Understanding Alzheimer’s and dementia
Özgür Onur from the University Hospital of Cologne also curbs the euphoria: “These are not miracle cures.” However, the neurologist adds: “But something is happening: for the first time we have studies that show effects.” And Johannes Levin from the German Center for Neurodegenerative Diseases (DZNE) and the Munich Ludwig Maximilians University (LMU) says: “We have learned a lot. We now have a very good feeling for where it might be worthwhile to start therapeutically.”
The need is enormous: Alzheimer’s is by far the most common form of dementia worldwide. In Germany alone, it is estimated that around a million people are sick – and the number is increasing due to population development. Researchers have been searching for the cause of the disease for decades. But there is one circumstance in particular that makes research extremely difficult: the damage to the brain initially goes unnoticed for many years; by the time it is diagnosed, the dementia is already well advanced. “After that, people on average don’t live another ten years,” says Levin.
At the time of diagnosis, the brains of Alzheimer’s patients contain noticeable deposits of two proteins: Amyloid beta (Abeta) has accumulated between the nerve cells to form so-called plaques. Abeta is a fragment of a protein that is widespread in the animal kingdom and whose function is currently unknown. In addition, the protein tau has accumulated in the nerve cells to form so-called fibrils.
Antibodies remove the plaques very strongly
For years, much of the research community was divided into two camps, which suspected one of the two proteins – either Abeta or tau – as the cause of the symptoms. A disease mechanism is now emerging in which both deposits are significantly involved. “Abeta and tau belong together,” says Levin.
Evidence of this was provided not least by the studies on the three antibodies: These aim to clear the characteristic Abeta deposits between the neurons. The active ingredients do this extremely effectively – especially donanemab. In the 18-month study, the antibody removed the plaques in a large proportion of the 860 participants to such an extent that Abeta was no longer detectable. “A fascinating finding,” says the Cologne expert Onur.
The big but: The effect on the disease itself remained manageable – its progression was slowed by up to 35 percent compared to placebo therapy, depending on the subgroup. In other words, the dementia continued to progress, but not quite as quickly. DGN expert Dodel doubts that those affected could even notice the effect.
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There are also two further disadvantages of the therapy: The effort is considerable. The active ingredient is administered intravenously every four weeks, lasting two hours each time. Above all, the side effects are potentially dangerous, as the study team led by John Sims from the pharmaceutical company Eli Lilly and Company writes in “JAMA”.
Almost one in four participants (24 percent) experienced swelling and edema in the brain, and three patients died as a result. Therefore, treatment must be monitored, for example through regular magnetic resonance imaging (MRI) examinations. “Ultimately, more data will be needed to determine whether the dangers of these drugs are outweighed by their modest clinical benefits,” says a JAMA commentary on the study.
In Levin’s opinion, the reason why the therapy does not slow down the progression of the disease more significantly despite the successful removal of Abeta is due to the tau protein. A variant of this accumulates in the nerve cells and, according to many experts, is the actual cause of cell death.
Tau fibrils probably cause nerve degeneration
“We now know the sequence of events very well,” says Levin. “We know that the pathological processes that lead to Alzheimer’s disease begin about 20 years before the first symptoms.”
Accordingly, the process initially starts with the formation of Abeta plaques in the brain. Although these deposits do not appear to damage the nerve cells directly, they do lead to the formation of tau fibrils in the cells – through a process that is not yet fully understood – which is probably the actual cause of neurodegeneration. This is supported by the fact that the area of the brain affected by tau fibrils in Alzheimer’s patients corresponds exactly to the region whose function is restricted, explains Levin. In addition, the antibody donanemab helps best those people who still have few tau fibrils in their nerve cells.
For therapy, this means: Even if the Abeta deposits are removed from the brain, the tau cascade could already have taken on a life of its own. Then it would be too late to stop cell death simply by clearing away Abeta.
If this model is correct, the tau fibrils would also have to be removed. But these proteins – in contrast to plaques – are not located outside the nerve cells, but inside. “Taw is harder to tackle,” says Dodel.
Combination therapy as the key to success
Since dead cells in the brain do not renew themselves, Alzheimer’s disease cannot be reversed. But: One day – perhaps not too far away – it is hoped that the progression will be stopped.
The key to this, experts agree, would be a combination therapy: This should clear away both Abeta and tau deposits in the brain. In addition, the treatment should inhibit the inflammatory processes in the brain associated with the disease as well as the changes in the blood vessels.
Such a combination therapy would make most sense if it were started very early – if possible before the first damage occurs. But to do this you would have to recognize the onset of dementia long before the first symptoms appear.
One would help reliable blood test, in which blood is taken and then analyzed in the laboratory. This is exactly what part of Alzheimer’s research is currently aiming at. The diagnosis of the disease is currently based – in addition to memory tests – on analyzes of the cerebrospinal fluid (cerebrospinal fluid) and examinations using positron emission tomography (PET) for Abeta and tau. This is complex, expensive and very stressful for patients. A good blood test should help to early identify those people who could benefit from preventive treatment.
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Although many such tests are being tested, a reliable biomarker – i.e. a parameter that can be measured in the blood to diagnose Alzheimer’s – is still missing. Already two years ago the so-called Precivity-Bluttest Approved for the USA and the EU. It is intended to show patients with the first symptoms whether it is Alzheimer’s. The test primarily determines the relationship between Abeta variants 42 and 40.
Im “PNAS” journal At the end of 2022, a team led by Valerie Daggett from the University of Washington in Seattle also presented such a test that can not only identify Alzheimer’s patients, but should also start years before the first symptoms appear. However, it was only tested in a proof of concept on just under 380 blood samples – and not in clinical practice.
Other tests focus on specific forms of the tau protein. “There are many publications that blood tests are becoming more reliable,” says Dodel. Onur adds that individual test procedures have already achieved good results, but they are still too imprecise for practical use.
In the future, Alzheimer’s will be treated as a chronic disease
In any case, it is unclear what a functioning early test would mean for the health system: Dodel will go into action if it is approved by the EU Lecanemab antibody from a price of 20,000 to 30,000 euros per year – with potentially 150,000 to 200,000 people eligible. In addition, those affected would have to be examined closely given the frequent side effects. “The costs would put a lot of strain on the German health system,” says Dodel.
In the long term, Munich expert Levin believes that Alzheimer’s disease will become a chronic disease, similar to diabetes 2. “It will be possible to stabilize the disease to such an extent that people do not lose their independence,” believes the doctor, who is working on one Companies involved in the search for active ingredients.
However, that will probably take some time: even if an effective active ingredient were found, according to the researcher, it would probably be several years before it came onto the market. “We are on the right track,” says Levin.
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