A paper published online today in Nature Medicine finds that in familial Alzheimer’s disease, blood levels of neurofilament light (NfL) rise 16 years before the predicted age of onset. Scientists led by Mathias Jucker, German Center for Neurodegenerative Diseases, Tübingen, measured the protein in serial samples given by participants in the Dominantly Inherited Alzheimer Network (DIAN). They found that the change in NfL level over time, rather than the absolute amount, was the best correlate of cortical thinning and better prognostic marker. While not specific for AD, NfL could help track progression of the disease and serve as a marker in clinical trials, wrote the authors. Alzforum covered these findings when co-first author Stephanie Schultz, Washington University School of Medicine, St. Louis, presented them at the Alzheimer’s Association International Conference in Chicago last year (Aug 2018 conference news).
- Neurofilament light is elevated in blood in people with familial Alzheimer’s.
- Levels begin to change 16.2 years before onset of disease.
- Rate of change peaks in people about to convert.
“The data look wonderful,” said Henrik Zetterberg, University of Gothenburg, Sweden, who was not involved in the research. “You can, with a simple blood test, follow the intensity of the neurodegenerative process.” In an editorial to be published in the February Nature Medicine, Zetterberg along with Jonathan Schott, University College London, noted that plasma NfL could track ongoing neurodegeneration in a wide range of neurodegenerative disorders and might help determine when to start disease-modifying therapies.
Schultz and co-first authors Oliver Preische and Anja Apel in Tübingen used a single-molecule array immunoassay to measure NfL in the CSF and serum of 243 people who carried mutations in the Aβ precursor protein (APP), presenilin 1 (PSEN1), or PSEN2. They compared these against CSF and serum from 162 noncarrier controls. During the two- to three-year period following baseline measures, 196 volunteers completed one to five follow-up visits.
Baseline data set carriers and noncarriers apart as early as 6.8 years before disease onset. However, when the researchers calculated the rate of change across serial blood samples, they found that climbing NfL predicted disease almost a decade sooner, some 16.2 years before onset. Rates of change were highest in people who became demented.
In familial AD mutation carriers, rates of change of NfL correlated with cortical thinning in the precuneus—an area reported to be sensitive to AD progression (Benzinger et al., 2013). However, NfL changes did not track with deposition of Aβ there, suggesting that once neurodegeneration begins, it continues independently of Aβ pathology.
It is now important to determine what interval is necessary to measure the rate of change, Jucker wrote to Alzforum. That will depend on the EYO (see image above). He also cautioned that the molecular process behind the NfL increase is still unclear. The authors noted that it will be important to translate these findings to sporadic Alzheimer’s disease and other cerebral proteopathies and to consider comorbidities in those with late-onset disease, since they may influence levels of NfL in the blood.—Gwyneth Dickey Zakaib
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