Early prediction of progression of Alzheimer's disease in the blood

Years before the symptoms of Alzheimer's disease manifest themselves, the brain begins to change and the neurons break down slowly. Scientists from the German Center for Neurodegenerative Diseases (DZNE), the Institute of Clinical Research on the Brain (HIH) of Hertie and the University Hospital Tübingen now demonstrate that a protein present in the Blood can be used accurately well long before the appearance of the first clinical signs. This blood marker offers new possibilities for testing therapies. The study was conducted in cooperation with an international research team and published in the journal Nature Medicine.

"The fact that there is still no effective treatment for Alzheimer's disease is partly due to the fact that current treatments start far too late," said Mathias Jucker, senior researcher at the DZNE site in Tuebingen. at the HIH Institute. He led the ongoing study. To develop better treatments, scientists therefore need reliable methods to monitor and predict the course of the disease before the onset of symptoms such as changes in memory. A blood test is better suited for this than e. g. costly brain tests.

Recently, some blood tests have progressed. Most of them are based on so-called amyloid proteins. In Alzheimer's disease, amyloid proteins accumulate in the brain and also manifest themselves in the blood. However, Jucker and his colleagues take a different approach. "Our blood test is not about amyloid, but what it does in the brain, which is neurodegeneration, in other words, we're looking at the death of neurons," Jucker says. .

When brain cells die, their remains can be detected in the blood. "Normally, however, such proteins are rapidly degraded in the blood and are therefore not very suitable as markers of a neurodegenerative disease," Jucker explains. "One exception, however, is a small piece of neurofilament that is surprisingly resistant to this degradation." The blood test of Jucker and his colleagues is based on this protein. In the present study, scientists have shown that the neurofilament accumulates in the blood well before the onset of clinical symptoms (that is, already during the so-called preclinical phase) and reflects very well evolution of the disease and can predict future evolution.

The study is based on data and samples from 405 individuals badyzed as part of an international research collaboration: the "predominantly hereditary Alzheimer's Network" (DIAN). In addition to the DZNE, the HIH and the University Hospital of Tuebingen, the faculty of medicine of the University of Washington in St. Louis (USA) and other institutions around the world are involved. This network studies families in which Alzheimer's disease already occurs in middle age due to certain genetic variations. Genetic badysis can predict with great precision if and when a family member will develop dementia.

Jucker and his colleagues monitored the development of neurofilament levels in these individuals from year to year. Until 16 years before the calculated appearance of dementia symptoms, there were noticeable changes in the blood. "This is not the absolute concentration of neurofilaments, but its time course, which is significant and can predict the future course of the disease," Jucker says. In fact, in subsequent research, scientists have shown that changes in neurofilament concentration accurately reflect neuronal degradation and predict the course of brain damage. "We were able to predict brain loss and cognitive changes two years later," Jucker said.

Although it appeared that the rate of change in neurofilament concentration was closely related to brain degradation, the correlation with the deposition of toxic amyloid proteins was much less pronounced. This supports the hypothesis that although amyloid proteins trigger disease, neuronal degradation occurs independently.

Neurofilaments accumulate in the blood not only in Alzheimer's disease, but also during other neurodegenerative disorders. Thus, the test is only appropriately conditional to diagnose Alzheimer's disease. "However, the test accurately shows the evolution of the disease and thus constitutes a powerful instrument to study new therapies for Alzheimer's disease in the context of clinical trials," says Jucker.

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Preische O, SA Schultz, Apel A, et al. (2019): "Dynamics of serum neurofilaments predicts neurodegeneration and the clinical course of presymptomatic Alzheimer's disease" Nature Medicine, DOI: 10.1038 / s41591-018-0304-3

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