Years before symptoms of Alzheimer's disease manifest, the brain starts changing and neurons are slowly degraded. Scientists at the German Centre for Neurodegenerative Diseases (DZNE), the Hertie Institute for Clinical Brain Research (HIH) and the University Hospital Tuebingen now show that a protein found in the blood can be used to precisely monitor disease progression long before first clinical signs appear. This blood marker offers new possibilities for testing therapies.
"The fact that there is still no effective treatment for Alzheimer's is partly because current therapies start much too late," says Mathias Jucker, a senior researcher at the DZNE's Tuebingen site and at the HIH. He headed the current study. In order to develop better treatments, scientists therefore need reliable methods to monitor and predict the course of the disease before symptoms such as memory changes occur. A blood test is better suited for this than expensive brain scans for example.
Recently, there was some progress in the development of such blood tests. Most of them are based on so-called amyloid proteins. In Alzheimer's disease, amyloid proteins accumulate in the brain and also occur in the blood. However, Jucker and his colleagues take a different approach. "Our blood test does not look at the amyloid, but at what it does in the brain, namely neuro-degeneration. In other words, we look at the death of neurons," says Jucker.
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 for a neuro-degenerative disease," explains Jucker. "An exception, however, is a small piece of so-called neuro-filament that is surprisingly resistant to this degradation."
The blood test of Jucker and colleagues is based on this protein. In the current study, the scientists show that neuro-filament accumulates in the blood long before the onset of clinical symptoms (already during the so-called pre-clinical phase) and that it very sensitively reflects the course of the disease and enables predictions on future developments.
The study is based on data and samples from 405 individuals that were analysed within an international research collaboration: the "Dominantly Inherited Alzheimer Network" (DIAN). In addition to the DZNE, the HIH and the University Hospital Tuebingen, the Washington University School of Medicine in St Louis and other institutions all over the world are involved. This network investigates families in which Alzheimer's disease already occurs in middle age due to certain gene variations. Genetic analyses allow very accurate predictions as to whether and when a family member will develop dementia.
Jucker and his colleagues monitored the development of neuro-filament concentration in these individuals from year to year. Up to 16 years before the calculated onset of dementia symptoms, there were noticeable changes in the blood. "It is not the absolute neuro-filament concentration, but its temporal evolution, which is meaningful and allows predictions about the future progression of the disease," says Jucker. In fact, in further investigations, the scientists showed that changes in neuro-filament concentration reflect neuronal degradation very accurately and allow predictions on how brain damage will develop. "We were able to predict loss of brain mass and cognitive changes that actually occurred two years later," says Jucker.
While it turned out that the rate of change in neuro-filament concentration was closely linked to brain degradation, correlation with the deposition of toxic amyloid proteins was far less pronounced. This supports the assumption that although amyloid proteins are triggers of disease, neuronal degradation occurs independently.
Neuro-filaments accumulate in the blood not only in Alzheimer's but also in the course of other neuro-degenerative disorders. Thus, the test is only conditionally suitable for diagnosing Alzheimer's. "However, the test accurately shows the course of the disease and is therefore a powerful instrument for investigating novel Alzheimer's therapies in clinical trials," says Jucker.
Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer’s disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease, which supports its potential utility as a clinically useful biomarker.
Oliver Preische, Stephanie A Schultz, Anja Apel, Jens Kuhle, Stephan A Kaeser, Christian Barro, Susanne Gräber, Elke Kuder-Buletta, Christian LaFougere, Christoph Laske, Jonathan Vöglein, Johannes Levin, Colin L. Masters, Ralph Martins, Peter R Schofield, Martin N Rossor, Neill R Graff-Radford, Stephen Salloway, Bernardino Ghetti, John M Ringman, James M Noble, Jasmeer Chhatwal, Alison M Goate, Tammie LS Benzinger, John C Morris, Randall J Bateman, Guoqiao Wang, Anne M Fagan, Eric M McDade, Brian A Gordon, Mathias Jucker
[link url="https://www.dzne.de/en/news/public-relations/press-releases/press/early-prediction-of-alzheimers-progression-in-blood/"]DZNE – German Centre for Neurodegenerative Diseases material[/link]
[link url="https://www.nature.com/articles/s41591-018-0304-3"]Nature Medicine abstract[/link]