The crucial question in Alzheimer's research

13.09.2022 17:25

What do you think about the amyloid hypothesis? This is currently one of the key questions in Alzheimer's research. Researchers around the world are discussing whether removing certain protein deposits in the brain, known as amyloid plaques, can cure the most common form of dementia. Aduhelm, a drug that breaks down these plaques, has been available since June 2021. However, the drug was not approved in Europe. Against this background, the research field is eagerly awaiting study results from two other active ingredients that work according to a very similar principle. The results are announced for autumn. On the occasion of World Alzheimer's Day on September 21st, the non-profit Alzheimer Research Initiative (AFI) provides information about the current debates in Alzheimer's research.

Alzheimer's disease is characterized by harmful protein deposits called amyloid plaques and tau fibrils. They play a role in the death of nerve cells in the brain, which causes memory loss and disorientation in Alzheimer's disease. This is undisputed in research. However, there is disagreement as to whether amyloid deposits in particular are the cause of the disease and represent a suitable target for drug therapy.

No approval for Alzheimer's drug in Europe

This question has been hotly debated in specialist circles since Aduhelm was approved in the USA. Because Aduhelm removes the harmful amyloid deposits in the brain. However, this does not improve the patient's memory performance. Because of this lack of proof of effectiveness, the European Medicines Agency (EMA) did not approve the approval of Aduhelm in Europe and therefore also in Germany in December 2021.

“I find this decision absolutely understandable,” comments Prof. Stefan Teipel, head of clinical research at the Rostock/Greifswald site of the German Center for Neurodegenerative Diseases (DZNE). “The study results simply weren’t particularly convincing in terms of improving cognition.”

The amyloid hypothesis has played a major role in Alzheimer's research worldwide in recent decades and many pharmaceutical companies have relied on different amyloid antibodies. Five active ingredients are currently being tested in advanced phase III studies for the treatment of Alzheimer's disease. Crucial study results are expected for donanemab and lecanemab, two of these antibodies, in the fall. Studies with similarly functioning active ingredients have failed in the past.

Why don't amyloid antibodies improve cognition?

The researchers do not know why the antibodies remove the harmful proteins but still do not improve the cognition of those affected. One reason could be that the active ingredients are administered too late in the course of the disease and the changes in the brain have already progressed too far by then. It is also discussed that the period in which the active ingredients were previously taken was too short to have a positive effect on the test subjects' cognition. Further studies and research projects are needed to find answers to these questions.

In the research field, more and more voices are being raised that point out that it is not enough to just focus on eliminating amyloid. “The amyloid hypothesis dominated research for a long time. However, in my opinion, such an approach is too one-dimensional and does not answer the question of where the amyloid comes from and what the actual causes of the disease are,” says Prof. Thomas Arendt, head of the Paul Flechsig Institute for Brain Research at the University of Leipzig and chairman of the Scientific Advisory Board of the AFI.

The causes of Alzheimer's disease are still unclear

The search for a suitable active ingredient is so difficult because the cause of Alzheimer's disease is not yet fully understood. The disease begins with the first changes in the brain up to twenty years before the first symptoms appear. The deposits of amyloid and tau are part of a number of processes in the brain that are subsequently determined. How these different disease mechanisms arise and intertwine over decades can no longer be easily understood in retrospect. “With an illness lasting up to 30 years, it is unlikely that you will see the causes, you will only see the consequences. “If a house burns down, you can’t tell from the ashes of the house why it burned down,” explains Arendt.

It is therefore important not only to focus on one disease mechanism with amyloid deposits, but also to take into account other characteristic features and possible causes of the disease, such as inflammatory processes, metabolic or circulatory disorders, environmental influences and genetic factors. It is becoming increasingly clear that there is no single drug that will cure Alzheimer's in every patient in every phase of the disease. Future Alzheimer's therapy will combine different approaches in order to stop the individually different disease processes as effectively as possible, depending on the stage of the disease. Accordingly, there is increasing research into combination therapies that target different disease mechanisms at the same time.

Why did the house burn down? Or: What happens next with the amyloid hypothesis?

And what happens next with the amyloid hypothesis? Teipel, who is also a member of the AFI Scientific Advisory Board, relies on a combined treatment approach that targets not only amyloid but also tau deposits: “Without amyloid, tau is probably not a major problem and conversely, tau without amyloid is probably not a major problem problematic. In combination, however, amyloid enables tau to spread throughout the entire brain. That's why I think a combination therapy that targets tau and amyloid at the same time is promising." The Alzheimer's researcher does not expect a fundamental breakthrough from the pending study results on the amyloid antibodies lecanemab and donanemab, but at least positive signals that underpin the approach of such a combination therapy .

So we don't yet know why the house burned down. The Alzheimer Research Initiative aims to find as many answers as possible to the remaining open questions through independent funding of basic research. “The AFI makes an important contribution to research because it is interdisciplinary, has patients in mind and also finances projects outside the research mainstream that are perhaps a little riskier, but at the same time are very important for gaining fundamental knowledge,” emphasizes Teipel.