Abstract Details

To assess plasma neurofilament light polypeptide (NfL) levels up to 23 years before amyotrophic lateral sclerosis (ALS) and relation to ALS risk.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a relatively rapid time from onset of symptoms to diagnosis. Neurofilament light polypeptide (NfL) is consistently elevated in symptomatic ALS and has been found to be elevated in samples collected as much as 5 years before diagnosis. However, to date the time prior to ALS that NfL has been examined has been limited.

We conducted a nested matched case–control study within the Danish Diet, Cancer and Health cohort, including 166 ALS cases and 332 controls matched on age and sex. Plasma samples collected 0.4-23.2 (median=14.1) years before diagnosis were analyzed for NfL using the Olink Target 96 Neurology panel. Associations between NfL and ALS were assessed using conditional logistic regression. Discriminatory performance was evaluated using receiver operating characteristic curves (ROC).

NfL levels were elevated in ALS cases relative to controls up to 14.6 years (median of times between 5 and 23 years) before ALS diagnosis. Among those with blood samples collected 5-14.6 years before ALS, the odds ratio for ALS per sd higher NfL was 1.7 (95% CI: 1.2-2.3). The area under the curve (AUC) for ALS discrimination by NfL among those with blood collected <5 and 5-14.6 years before ALS were 0.78 (17/34 cases/controls) and 0.63 (75/150 cases/controls), respectively.

While prior work has suggested elevated plasma NfL up to 5 years prior to ALS, we find elevation much earlier. This suggests a much longer ALS prodrome than generally thought. Assuming other biomarker changes may also occur earlier, this raises the possibility of identifying at-risk individuals early that could benefit epidemiologic analyses, prevention efforts, and clinical trials.