Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) concentrations identify asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.

Methods: Baseline plasma NfL concentrations were measured with Simoa in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN and MAPT mutation carriers and non-carriers from the same families were classified by disease severity [asymptomatic, prodromal and full phenotype] using the CDR^® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module (CDR^®+NACC-FTLD). Linear mixed effect models related NfL to clinical variables.

Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or subsequent disease progression compared to non-progressors (original: 11.4 ± 7 pg/mL vs. 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs. 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR^®+NACC-FTLD sum of boxes scores, neuropsychological function and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.

Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression, and is a potential tool to select participants for prevention clinical trials.

Classification of evidence: This study provides Class I evidence that in familial FTLD, elevation of plasma NfL predicts short-term risk of clinical progression.

The data was collected through clinical evaluation, measurement of biomarker in plasma and volumetric quantification of brain MRI.

These data supplement those in the main manuscript and are used to support the findings and conclusions.