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. 2025 Aug;106(4):1337-1354.
doi: 10.1177/13872877251352103. Epub 2025 Jul 2.

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

Ella Liu  1 , Sherri Lee Jones  2 , Victoria Light  3 , Charlotte Teunissen  3 , Arabella Bouzigues  4 , Lucy L Russell  4 , Phoebe H Foster  4 , Eve Ferry-Bolder  4 , John C van Swieten  5 , Lize C Jiskoot  5 , Harro Seelaar  5 , Raquel Sanchez-Valle  6 , Robert Laforce  7 , Caroline Graff  8 , Daniela Galimberti  9 , Rik Vandenberghe  10 , Alexandre de Mendonça  11 , Pietro Tiraboschi  12 , Isabel Santana  13 , Alexander Gerhard  14   15   16 , Johannes Levin  17   18   19 , Sandro Sorbi  20 , Markus Otto  21 , Chris R Butler  22 , Isabelle Le Ber  23 , Elizabeth Finger  24 , Maria Carmela Tartaglia  25 , Mario Masellis  26 , James B Rowe  27 , Matthis Synofzik  28 , Fermin Moreno  29 , Barbara Borroni  30 , Henrik Zetterberg  31 , Jonathan D Rohrer  4 , Simon Ducharme  2   32 ; Genetic Frontotemporal Dementia Initiative (GENFI) and Banque Signature (BbS)
Affiliations

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

Ella Liu et al. J Alzheimers Dis. 2025 Aug.

Abstract

BackgroundGenetic 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.ObjectiveThis 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.MethodsData (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).ResultsBlood-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).ConclusionsNfL holds potential as a blood-based biomarker for symptomatic genetic FTD carriers, with moderate accuracy to distinguish PPD from mild forms including C9orf72.

Keywords: Alzheimer's disease; biomarkers; diagnosis; frontotemporal dementia; neurofilament proteins.

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Conflict of interest statement

Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SD conducts sponsored clinical trial research (Biogen, NovoNordisk, Innodem Neurosciences, Janssen, Alnylam) and has received advisory/speaker fees (Eisai, QuRALIS, Eli Lilly). JBR provides consultancy unrelated to the current work to Asceneuron, Astronautx, Astex, Curasen, CumulusNeuro, Wave, SVHealth, and has research grants from AZ-Medimmune, Janssen, and Lilly as industry partners in the Dementias Platform UK. The other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Blood-based Log NfL levels in symptomatic genetic FTD carriers and PPD. Mean plasma log NfL in symptomatic GENFI C9orf72, GRN, and MAPT mutation carriers compared to mean serum log NfL in BbS PPD patients. Horizontal line represents the benchmark mean plasma log NfL in GENFI noncarrier controls. ***p < 0.001 compared to BbS PPD patients.
Figure 2.
Figure 2.
Blood-based Log NfL levels in late presymptomatic genetic FTD carriers and PPD. Mean plasma log NfL in late presymptomatic GENFI C9orf72, GRN, and MAPT mutation carriers compared to mean serum log NfL in BbS PPD patients. Horizontal line represents the benchmark mean plasma log NfL in GENFI noncarrier controls. *p < 0.05 compared to BbS PPD patients.
Figure 3.
Figure 3.
Blood-based Log NfL levels in mildly symptomatic (0 < FTLD-CDR-SOB-NM < 4) Genetic FTD Carriers and PPD. Mean plasma log NfL in mildly symptomatic GENFI genetic mutation carriers with 0 < FTLD-CDR-SOB-NM < 4 versus mean serum log NfL in BbS PPD patients. Horizontal line represents the benchmark mean plasma log NfL in GENFI noncarrier controls. ***p < 0.001 compared to BbS PPD patients.
Figure 4.
Figure 4.
Blood-Based Log NfL levels in noncarrier controls and PPD. Mean plasma log NfL in noncarrier controls versus mean serum log NfL in BbS PPD patients. ***p < 0.001 compared to PPD.
See this image and copyright information in PMC

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