Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Feb 20;11(1):19.
doi: 10.1186/s13195-019-0472-5.

Longitudinal measurement of serum neurofilament light in presymptomatic familial Alzheimer's disease

Philip S J Weston  1 , Teresa Poole  2   3 , Antoinette O'Connor  2 , Amanda Heslegrave  4 , Natalie S Ryan  2 , Yuying Liang  2 , Ronald Druyeh  2 , Simon Mead  5 , Kaj Blennow  6 , Jonathan M Schott  2 , Chris Frost  2   3 , Henrik Zetterberg  4   6 , Nick C Fox  2   4
Affiliations

Longitudinal measurement of serum neurofilament light in presymptomatic familial Alzheimer's disease

Philip S J Weston et al. Alzheimers Res Ther. .

Abstract

Background: To investigate how serum neurofilament light (NfL) concentration changes through the course of disease in familial Alzheimer's disease (FAD) and to assess when NfL concentration first increases.

Methods: NfL was measured using an ultrasensitive immunoassay in 117 serum samples from 61 individuals from families with PSEN1 or APP mutations in a longitudinal study (mean ± SD = 1.9 ± 1.1 visits/patient; inter-visit interval = 1.8 ± 1.1 years). The relationship between NfL concentration and estimated years to/from symptom onset (EYO) was modelled using linear regression, including all time points and robust standard errors to allow for repeated measurements, adjusting for age at visit and sex. Also, for the 27 participants who became symptomatic (during or before the study), NfL concentration was also modelled against known actual years to/from onset (AYO).

Results: There were 15 non-carriers and 46 mutation carriers (21 symptomatic; 25 presymptomatic). NfL concentration was increased (p = 0.045) in mutation carriers compared with non-carriers 15 years prior to expected symptom onset, increasing progressively thereafter. There was a significant inter- and intra-individual variability in the longitudinal pattern of change. Modelling NfL for the 27 mutation carriers with known AYO also showed a progressive increase over time.

Conclusions: There is evidence that serum NfL is increased more than a decade before the onset of clinical symptoms in FAD and rises thereafter. While there is variability in change over time, both within and between individuals, and more work is needed to understand the sources of this variability, serum NfL remains a promising, accessible biomarker of early neurodegeneration in presymptomatic Alzheimer's disease.

Keywords: Search terms; [111] blood; [111] longitudinal; [111] neurofilament light; [26] Alzheimer’s disease; [91] autosomal dominant.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the Queen Square Research Ethics Committee and all participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

K. Blennow has served as a consultant or at advisory boards for Alzheon, Eli Lilly, Fujirebio Europe, IBL International, Novartis, and Roche Diagnostics and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. J. Schott has received research funding from AVID Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), has consulted for Roche Pharmaceuticals and Eli Lilly, and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. H. Zetterberg is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg, and has served on scientific advisory boards of Roche Diagnostics, Eli Lilly, Samumed, CogRx, and Wave. N. Fox reports fees (paid to University College London) for consultancy from Janssen, Eli Lilly, Novartis, Sanofi, Roche, and GlaxoSmithKline and for serving on a data monitoring committee for Biogen. The other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Serum NfL against EYO. Mutation carriers are represented in red and non-carriers in black. a Measured values of serum NfL concentration against EYO. Those measurements that belong to the same individual are connected by a line. To ensure it is not possible to identify any of the individual asymptomatic participants (based on their EYO) and so determine their mutation status, five outlying participants have been removed and a jitter of up to ± 2 years has been applied to all remaining participants. Also, for the three individuals who donated more than three samples, only their first three measurements are shown. b Geometric mean NfL modelled against EYO, for someone of average age (40.9 years) and sex (half male/female). Dotted lines indicate 95% confidence intervals. EYO estimated years to/from symptom onset. The geometric mean is the exponential of a mean calculated on the log scale
Fig. 2
Fig. 2
Serum NfL against AYO. a (In red) measured serum NfL concentration against AYO, for the 27 mutation carriers who have already developed symptoms (either before or during the study). Those measurements that belong to the same individual are connected by a line. No jitter has been applied. The black broken line represents the mean serum NfL concentration for non-carriers, with dotted lines for ± 1.96 SD, calculated on the log scale and back transformed. By showing ± 1.96 SD, we are indicating a reference range within which 95% of the observed values are expected to lie. b Geometric mean NfL modelled against AYO, for someone of average age (40.9 years) and sex (half male/female). The black broken line represents the geometric mean serum NfL concentration for non-carriers. Dotted lines indicate 95% confidence intervals (i.e. on repeated random sampling, 95% of CIs calculated in this way will include the true population geometric mean). AYO actual years to/from symptom onset. The geometric mean is the exponential of a mean calculated on the log scale
See this image and copyright information in PMC

References

    1. Weston PSJ, Poole T, Ryan NS, Nair A, Liang Y, Macpherson K, et al. Serum neurofilament light in familial Alzheimer disease: a marker of early neurodegeneration. Neurology. 2017;89(21):2167–2175. doi: 10.1212/WNL.0000000000004667. - DOI - PMC - PubMed
    1. Sanchez-Valle R, Heslegrave A, Foiani MS, Bosch B, Antonell A, Balasa M, et al. Serum neurofilament light levels correlate with severity measures and neurodegeneration markers in autosomal dominant Alzheimer's disease. Alzheimers Res Ther. 2018;10(1):113. doi: 10.1186/s13195-018-0439-y. - DOI - PMC - PubMed
    1. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol. 2016;15(13):1326–1335. doi: 10.1016/S1474-4422(16)30193-4. - DOI - PubMed
    1. Rohrer JD, Woollacott IO, Dick KM, Brotherhood E, Gordon E, Fellows A, et al. Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology. 2016;87(13):1329-36. - PMC - PubMed
    1. Huber PJ. Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and Probability. 1967. The behavior of maximum likelihood estimates under nonstandard conditions; pp. 221–233.

Publication types

LinkOut - more resources