Accuracy of blood-based neurofilament light to different genetic frontotemporal dementia from primary psychiatric disorders

Background: Genetic frontotemporal dementia (FTD) along with Alzheimer's disease (AD), is one of the most prevalent early-onset dementias. The differential diagnosis of FTD from primary psychiatric disorder (PPD) has been challenging due to significant symptom overlap, particular as FTD often presents with prolonged psychiatric prodromes. Objective: This study aims to evaluate whether blood-based neurofilament light chain (NfL) can differentiate genetic FTD from PPD, and to determine a global clinical cutoff to differentiate genetic FTD carriers from PPD with high specificity and sensitivity. Methods: Data (ages 40–81) were obtained from FTD mutation carriers (GENFI; n = 474; n = 120 C9orf72, n = 114 GRN, n = 50 MAPT, n = 190 controls), and PPD (Biobanque Signature; n = 848). Blood-based NfL was measured with SIMOA HD-X (BbS) and SIMOA HD-1 (GENFI). Results: Blood-based NfL was higher in all symptomatic mutations compared to PPD. Mildly symptomatic (0 < FTLD CDR-SOB-NM < 4) C9orf72 and GRN carriers also had higher NfL. ROC curve revealed an optimal blood-based NfL cutoff of 22.1 pg/mL (J = 0.647) to distinguish symptomatic genetic FTD from PPD (78.5% sensitivity, 86.2% specificity, AUC = 0.908). For mildly symptomatic subjects, a cutoff of 16.2 pg/mL (J = 0.601) differentiated groups with 86.7% sensitivity and 73.5% specificity (AUC = 0.870). Conclusions: NfL holds potential as a blood-based biomarker for symptomatic genetic FTD carriers, with moderate accuracy to distinguish PPD from mild forms including C9orf72.