Plasma NfL rises up to 14.6 years before ALS diagnosis
In a nested case-control study, each standard deviation increase in plasma NfL was tied to 1.7-fold higher ALS odds 5 to 14.6 years before diagnosis.
Annals of Neurology
Researchers evaluated 166 people who later developed amyotrophic lateral sclerosis (ALS) and 332 matched controls from the Danish EPIC cohort. The team measured plasma neurofilament light polypeptide (NfL) in blood collected between 0.4 and 23.2 years before diagnosis, with a median timeframe of 14.1 years.
Plasma NfL levels were elevated in ALS cases up to 14.6 years prior to diagnosis. For blood sampled less than 5 years before diagnosis, each standard deviation increase in normalized NfL expression yielded an odds ratio of 3.8 for ALS, with an area under the curve of 0.78. Between 5 and 14.6 years prediagnosis, the odds ratio was 1.7, with an area under the curve of 0.63. Beyond 14.6 years, the odds ratio was 1.3.
Why it matters
Late-onset neurodegenerative diseases often feature prolonged prodromal phases characterized by subclinical neuronal damage. Demonstrating that markers of axonal injury rise over a decade prior to diagnosis suggests an extended window for early detection and intervention.
Caveats
This was an observational case-control study, and discriminatory performance was modest between 5 and 14.6 years before diagnosis. Additionally, the association between NfL levels and ALS risk was not statistically significant beyond 14.6 years.
The paper
Harvard University
Annals of Neurology · 2 Oct 2026