Early warning signs of Alzheimer

Mathias Jucker never really has a complete day off. The neuroscientist coordinates one of the world's most important studies on Alzheimer's disease: the DIAN study (Dominantly Inherited Alzheimer Network). "Almost everything we know about the course of the widespread sporadic Alzheimer's disease originally comes from the DIAN study's investigations into hereditary Alzheimer's," says Jucker. Around 80 people from 50 families participate in the German DIAN study, with over 500 participants worldwide, funded by the German Center for Neurodegenerative Diseases. The knowledge about the fate connects researchers and participants in the study; they know each other, call each other, even on weekends, as Jucker recounts.

The DIAN study is unique: it focuses on the few families worldwide where Alzheimer's disease is inherited due to a genetic mutation. These mutations inevitably lead to the disease.

Most people fall ill when they are between 40 and 50 years old - right around the time when the affected parent was also impacted. 'If someone carries such a mutation, we can predict with a very high degree of certainty when he or she will fall ill,' says Jucker. 'This predictability allows us to study these individuals long before they develop symptoms. It gives us a time window in which we can observe the onset of the disease, which would be very difficult in the general population because we do not know if or when someone will develop Alzheimer’s disease.'

A central goal of the DIAN study is the exploration of biomarkers for the early detection of Alzheimer’s disease. These include proteins such as beta-amyloid, tau, or neurofilament in the blood. 'We have found that these biological indicators change years before the symptoms appear,' explains Jucker. 'Misfolded beta-amyloid proteins, for example, accumulate in the form of plaques in the brain 20 years before the first clinical signs, which can then be detected in the blood.' These deposits seem to arise according to the domino principle: the first misfolded protein causes other proteins to also misfold, deposit in the brain, and destroy the nerve cells. Jucker's goal for the coming years is to identify this first fatal protein: 'If we succeed in pharmacologically shutting it down, we could successfully treat Alzheimer’s at a presymptomatic stage,' the neuroscientist is confident.

The discovery that Alzheimer's disease begins 20 years before the first symptoms appear has far-reaching consequences for research into potential therapeutic approaches. "We used to think it was enough to treat people at the first signs," says Jucker, "but now we know that it's probably more promising to start much earlier." For a long time, none of the drug developments achieved a breakthrough—no wonder, because by the time the typical symptoms begin, the brain has long since been irreparably damaged. "You have to know when this process begins and you have to stop it before it causes the first damage," Jucker summarizes what is probably the most important finding from DIAN.

The neuroscientist goes even one step further: He is convinced that in the not-too-distant future, there will even be screening for a predisposition to Alzheimer's. "For me, that's the only logical path. People without symptoms would be tested, and if their biomarker profile is abnormal, they would receive preventative treatment to prevent Alzheimer's from developing in the first place." This is made possible by technological advances in diagnostics. "Even today, we can analyze thousands of proteins from a single drop of blood. This allows us to identify patterns that indicate Alzheimer's or other neurodegenerative diseases," explains Jucker. And this so-called proteome could represent a revolutionary step in early detection of Alzheimer's in the future.

"Our specialty here in Tübingen is understanding the mechanisms behind biomarker changes," says Jucker. "We don't just want to know whether a protein is increasing, but also why this happens and what this means for the cells in the brain." The significance of the DIAN study thus extends far beyond Alzheimer's disease: It has revolutionized biomarker research and thus laid the foundation for other neurodegenerative diseases such as Parkinson's. "Many other research groups have used our model as a model," says Jucker. "They take the hereditary cases where it is known that they will develop the disease and look at the biomarkers." Researchers around the world are therefore increasingly looking for changes in the brain at the molecular level in neurodegenerative diseases beyond Alzheimer's dementia – with the aim of one day finding drugs to treat them.