Monday, 3 Oct 2022

Alzheimer’s agents floppten: Now the research in new ways

After numerous studies, there is still no effective remedy for Alzheimer’s. Also about the causes of the disease little is known. What are the new ways scientists keep track of what’s behind the failures, and why researchers still are confident.

It was a severe blow to the Alzheimer’s research: In March of this year, the company informed Biogen that it is established two clinical studies of a drug, with immediate effect. There is no prospect of success does not exist, the anti-body Aducanumab brake to the reduction of the spirit power as hoped, it was said to the grounds. It was far from the only bad news is that Alzheimer’s had to digest researchers.

In previous years, a number of clinical studies due to lack of efficacy of the active ingredient had been cancelled-candidates. All of the studies had one thing in common: they tested substances, which act on the protein amyloid beta (Abeta) – the molecule that accumulates in the brains of Alzheimer’s patients in the Form of so-called Plaques. Considered to be the hallmarks of the dementia disease.

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The basic idea: to Prevent the Deposit or grants to deposited Abeta-protein to leave the disease to prevent or stop it. Antibodies such as Aducanumab should be administered as agents to detect the protein structures and to attack – in accordance with the principle of a passive vaccination with antibodies against components of the disease. That should stop the mental decline.

“You have placed great hopes in these studies. It was thought that if this works, then we have found the Golden Nugget,“ says Hans-Ulrich Demuth Fraunhofer Institute for cell therapy and immunology (IZI) in Leipzig. "And then that happens."

The incentive to find a cure for the dementia disease, is large: in Germany Alone, approximately 1.7 million people with dementia live, according to the German Alzheimer society, the majority of them has Alzheimer’s. There should be no breakthrough in the prevention and therapy, could increase the number up to the year 2050 to about 3 million, showed calculations, taking into account the population development.

Rarely, the disease in humans is diagnosed under 60 years of age. However, Alzheimer’s is expected to begin already in middle age and progresses for decades, unnoticed, before the first symptoms occur. An effective drug, there is not, only a few drugs that slow down the progression of the disease, and the Lessening of mental abilities a little.

Abeta but not the solution to healing

The problem with the recent Failure of drug candidates solely on the fact that in the near future, no effective remedy against Alzheimer’s dementia is available is not. Many scientists are wondering whether you have been looking for the past few years, with the focus on Abeta at all in the right place after a starting point for a drug.

“The investigations that we have now, not indicate, at least to the fact that vaccination against Abeta in certain phases of the disease is effective,” says Alzheimer’s researcher Michael Heneka, Director of the clinic for Neurodegenerative diseases and geriatric psychiatry at the University of Bonn. Mourn not help in this Situation. Perhaps the shock turns out after the Failure as salutary. Because that opens up the possibility to rethink old approaches to research and test new. Both observed a new openness in the research community.

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The physician, who is head of the German center for Neurodegenerative diseases (DZNE) and the research group Neuroinflammation, researched since the mid-90s, the importance of inflammatory processes in Alzheimer’s disease. Heneka and his Team investigate, among other things, what is the role of the so-called innate immunity plays in the disease process, so innate defense and protection mechanisms. In the brain, this Form of immunity is mediated by so-called microglial cells.

“We have identified a mechanism that may be for the development of an Intervention,” said Heneka. “In principle, one tries to bring the microglia also contribute to the deposition of Amyloid-beta are not more pro-react flammable, but to continue to take care of the surrounding nerve cells and Amyloid deposits is actually clear – all of that is lost in the course of the disease.”

Abeta, the Protein which has been attacked in the failed trials of anti-bodies – is as a starting point for an active ingredient but not totally out of the race. “There are new approaches to antibody therapy,” says Fraunhofer researcher Demuth. In a Swedish study, currently being tested is an antibody, the have shown in a study to improve cognitive performance. “This is now the great hope in the Abeta-box.”

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Demuth co-founded in 1997, the biopharmaceutical company Probiodrug, today Vivoryon Therapeutics -working on the development of Alzheimer’s drugs. The scientists at that time showed that there is a subset of Abeta proteins that nerve cells damage and in Alzheimer’s disease play a prominent role. Since his move to the Fraunhofer Institute Demuth accompanied the exploration of an active substance in Vivoryon directed against these toxic Abeta variants, and currently a study is tested.

“For the emergence of this specific Abeta-Form of an enzyme is responsible, the glutaminyl zyklase, which is in the brain of affected patients is very high expressed,” explains Vivoryon CEO Ulrich DauER. “When we inhibit the enzyme, we prevent the formation of toxic Abeta variant. That’s our approach.“ From studies is known that the Occurrence of the toxic variant with the Occurrence of the disease symptoms depends on.

In a pilot Phase IIa study, in which primarily the safety of a drug is tested, researchers examined your inhibitor about three months in 120 patients. PQ912 proved to be safe. In addition, the researchers found that the cognitive functions are improved in this case, the memory performance of the patients. The active ingredient in larger studies more closely examined.

It is planned to win from the second quarter of next year, 460 patients from the US and Canada with mild cognitive impairment or mild Alzheimer’s disease for the study. For a total of 18 months and a half would get a placebo, the other PQ912. Also in Europe a similar study with 250 patients was planned.

Solution is not medication, but different approaches

A further starting point for the development of a Therapeutic agent, the Tau proteins offer. These proteins are components of the cell skeleton. According to the current understanding of the Abeta proteins that initiate the neurodegenerative process, while the Tau proteins are the exporting items – they make the nerve cells, ultimately, broken.

Antibodies against variants of the Tau-proteins to stop the disease process at this point. Of ideas and research approaches there is no shortage. Quasi-daily article with the new results to Alzheimer’s research projects and possible starting points appear in trade magazines for the drug search. Approximately 80 clinical studies of advanced Phase III run, according to the study register the EU is currently in Europe and the European economic area.

The Bonn researchers Heneka is convinced that there will not be a single drug for Alzheimer’s prevention or therapy in the future. “We will have to try to influence different disease mechanisms at the same time. There is no truth in the Tau field, or in the Abeta-field or in immunology.“

He compares the disease with a relay race, in which different mechanisms build upon each other. “If the first runner has finished his round and the staff has given, then you can look at the rumfeilen as you want – this will not affect the outcome of the race.” Vaccination against Abeta – perhaps the first runners in the race – would probably be too late, if the second runner had taken, so, for example, the immune system is already activated.

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To compound the problem, the disease in different areas of the brain are in different stages – also need to be taken into account. “The fundamental Problem is that you have to know the pathological characteristics, i.e., the Abeta-Plaques, the Tau Plaques, Neuroinflammation, but that he has not understood the relationships between these three features,” says endurance. After the recent Failure of the Abeta-studies, one should not rush to the next destination.

The importance of further basic research also Demuth refers. He is nevertheless confident that it will be in the coming years, decisive progress in the search for a drug and sees the setbacks of the past has left: “Without the failures, without the blind alleys that have opened since, we would never be where we are today. “

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