Neurofilament in Blood Foretells Early Onset Alzheimer’s

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.

Early Riser. Rate of change of serum NfL is higher in familial AD mutation carriers (red) than in controls (blue) beginning an estimated 16.2 years before disease onset (EYO). Dots represent change among individual DIAN participants, who each gave blood samples over an average of three years. [Courtesy of Preische et al., 2019. Nature Medicine.]

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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References

News Citations

  1. Blood Test for Neurofilament Light Chain Kicks Up Biomarker Research

Paper Citations

  1. Benzinger TL, Blazey T, Jack CR Jr, Koeppe RA, Su Y, Xiong C, Raichle ME, Snyder AZ, Ances BM, Bateman RJ, Cairns NJ, Fagan AM, Goate A, Marcus DS, Aisen PS, Christensen JJ, Ercole L, Hornbeck RC, Farrar AM, Aldea P, Jasielec MS, Owen CJ, Xie X, Mayeux R, Brickman A, McDade E, Klunk W, Mathis CA, Ringman J, Thompson PM, Ghetti B, Saykin AJ, Sperling RA, Johnson KA, Salloway S, Correia S, Schofield PR, Masters CL, Rowe C, Villemagne VL, Martins R, Ourselin S, Rossor MN, Fox NC, Cash DM, Weiner MW, Holtzman DM, Buckles VD, Moulder K, Morris JC. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4502-9. Epub 2013 Nov 5 PubMed.

Further Reading

Papers

  1. Sánchez-Valle R, Heslegrave A, Foiani MS, Bosch B, Antonell A, Balasa M, Lladó A, Zetterberg H, Fox NC. Serum neurofilament light levels correlate with severity measures and neurodegeneration markers in autosomal dominant Alzheimer's disease. Alzheimers Res Ther. 2018 Nov 3;10(1):113. PubMed.
  2. Mattsson N, Andreasson U, Zetterberg H, Blennow K, Alzheimer’s Disease Neuroimaging Initiative. Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol. 2017 May 1;74(5):557-566. PubMed.

Primary Papers

  1. Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, Gräber S, Kuder-Buletta E, LaFougere C, Laske C, Vöglein J, Levin J, Masters CL, Martins R, Schofield PR, Rossor MN, Graff-Radford NR, Salloway S, Ghetti B, Ringman JM, Noble JM, Chhatwal J, Goate AM, Benzinger TL, Morris JC, Bateman RJ, Wang G, Fagan AM, McDade EM, Gordon BA, Jucker M, Dominantly Inherited Alzheimer Network. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med. 2019 Feb;25(2):277-283. Epub 2019 Jan 21 PubMed.

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