Biomarker: Alzheimer's in the blood

Professor Christian Haass has been researching the basics of therapy for 30 years. His latest approach: stimulating the immune cells in the brain

Experimenting with one's own blood brought a frightening result: it contained a protein that one would have expected in people with Alzheimer's disease. Alzheimer's researcher Christian Haass believed that he himself would soon develop this form of dementia, which destroys memory, orientation and ultimately independence. And that at the age of 32. "I feared the worst for myself," says the molecular biologist, recalling his discovery in 1992.

A few days later, however, the next result reassured him. The supposed Alzheimer's mark beta-amyloid was also found in the blood of his colleagues. Haass had the real aha moment a few weeks later in the darkroom. "I knew straight away that this would change the entire area. And my future as a researcher is secured for the time being."

Why does amyloid beta form clumps in the brain?

What he saw allowed only one conclusion: Beta-amyloid is a normal protein in healthy people and is produced in many tissues. This paved the way for research into human cell cultures. The basis for finding out why beta amyloid forms clumps in the brain - the suspected cause of Alzheimer's. Haass fell into a previously unknown euphoria. "It has to be like cocaine. You get addicted." He and his colleagues worked feverishly day and night. "That was a bit dangerous," recalls Haass. He barely slept, didn't know much more about Boston than walking to the laboratory and back.

Disastrous loss: brain cells perish in Alzheimer's disease. Researchers and companies are looking for ways to stop this process. The first thing to do is to die off nerve cells in the hippocampus. This area is important for memory. Forgetfulness is therefore the harbinger of this dementia. In the end, the brain has shrunk by about a fifth.

© W & B / Astrid Zacharias

His daughter was born on the very day that the renowned journal Nature released its results for publication. A few hours later he was back in the laboratory. "I would never make that mistake again. I still resent that today," says Haass, who published three times in Nature in one year.

The immune system should help

"I'm either doing something right or not at all." This is Haass ’motto in life, who describes himself as a" nerd ". The English word often stands for very clever people who excessively cultivate their special interests and completely neglect social contacts. Weirdos who spend almost all of their time in front of the computer - or in the research laboratory. Haass is also a bird nerd. Even as a baby he crawled after the animals. His parents later told him that he only learned to walk in order to be able to follow them faster. Today the 59-year-old goes to a lake in Upper Bavaria almost every Saturday and Sunday to watch birds. "That gives me great pleasure. There is always something new to discover."

Since 2014 he has been the spokesperson at the Munich location of the German Center for Neurodegenerative Diseases. "I am overjoyed to have the institute here. Everything is there - from biophysics to the patient." Almost all of his team has been researching a new approach to stop Alzheimer's for several years. The immune system is supposed to be activated to effectively fight beta-amyloid clumps in the brain.

A long foreplay

The destructive process begins many years before the disease

Beta amyloid lumps Rope fibers Nerve cell death First symptoms dementia 0 10 20th 30th Time in years change

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Beta amyloid lumps

The body's own protein beta-amyloid forms clumps. It usually starts in middle age.

Rope fibers

The clumping causes a second change: the protein Tau forms fibers in nerve cells.

Nerve cell death

If too many tau fibers have accumulated, it comes to Death of the nerve cells that are affected.

First symptoms

The failure of cells leads to a pronounced forgetfulness as the first symptom.

dementia

It comes to dementia. Finally, many are affected completely dependent on outside help.

© W & B / Astrid Zacharias

Heated debate

Haass remembers well the specialist congress at which he presented the first results. The Alzheimer's immunology expert snapped at him, "Christian, your research is toxic to the young listeners in this room." Haass was speechless. Then he struggled. A heated debate broke out. He had contradicted the doctrine that immune reactions in the brains of Alzheimer's patients are always bad - and that future drugs should therefore suppress them.

The "Brain Prize" gave Haass a tailwind. In May 2018 he received the world's most important award for a neuroscientist. "The award could not have come on a better day. At the time, my nerves were pretty exhausted. The public displeasure with the allegedly unsuccessful amyloid research and the worst personal hostility in a prominent weekly newspaper pissed me off." For him, the price means confirmation that he is on the right track.

Attack Alzheimer's proteins: An antibody against beta-amyloid clumps showed a small positive effect on test subjects last autumn. In the USA, the authority is checking approval.

© W & B / Astrid Zacharias

First drugs against beta amyloid? Test results contradicting itself

But so far no active ingredient has brought the hoped-for success. "The amyloid hypothesis is buried," said neuroscientist Dr. George Perry from the University of Texas at San Antonio (USA) commented on a failed study in 2016. Haass thinks this is utter nonsense. "Anyone who claims such a thing is ignoring all of the genetic findings. But the facts cannot simply be swept under the table." In other words: genetic variants that promote the clumping of beta-amyloid lead to Alzheimer's very early in life. And variants that reduce production by 20 percent protect against this dementia.

Will the first drug against beta-amyloid be available soon after all? An approval process is to begin soon in the USA. But the present test results are contradictory, as are the reactions of the manufacturer: In March 2019, he broke off two studies with a total of over 3,200 participants because the therapy did not help those treated.

Influence immune cells: A company in the USA has recently been testing a new active principle on volunteers: immune cells in the brain are supposed to be activated to break down beta-amyloid clumps.

© W & B / Astrid Zacharias

To this day, herbs only relieve symptoms

Haass is outraged: "The test subjects learned about the discontinuation of the study from the press. This is not how the patients should be treated." They have not received any test active ingredients since the termination. Haass: "This is crazy! The companies pretend that the patients belong to them. But without test subjects, we will never become one
Bring drug to market. "

The company turned around in October. Another analysis had shown: In the highest dose, the drug definitely improves the ability to cope with everyday life independently. However, only in one of the two studies. Haass himself has seen many surprising twists and turns. For example the euphoria at the turn of the millennium when vaccination with beta-amyloid first showed success in animal experiments. "Back then, all the experts thought that now the drugs would come to the patients. And we Alzheimer's researchers can go home." But then came the many failures. To date there are only herbs that alleviate the symptoms - delay memory loss.

Haass himself doesn't like the word failure. "We learned something new with every test." However, the realization is frightening: the disease is likely to develop at least 20 years before the first symptoms. This makes the treatment extremely difficult. And also explains why previous studies have not been successful. Only now is the time ripe for meaningful drug tests. Biomarkers that the brain releases into the blood now help determine whether an active ingredient has an effect in the body.

A current study, for example, uses a blood biomarker to show that a substance against beta amyloid slows the death of nerve cells. Haass hopes that he will soon be able to test whether immune cells in the brains of Alzheimer's patients can be activated. "If that works, a lifelong dream would come true for me."

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