Plasma Proteomic Changes Reveal Distinct Biomarker Signatures in GRN and C9orf72 Frontotemporal Dementia

Developing robust biomarkers is crucial for genetic frontotemporal dementia (FTD), especially with emerging therapeutic trials. Current diagnostic methods often rely on clinical presentation, which can be heterogeneous and overlap with other neurodegenerative conditions. Identifying specific blood-based biomarkers that reflect the underlying pathophysiology of genetic FTD, particularly for mutations in the GRN and C9orf72 genes, could enable earlier diagnosis, disease monitoring, and personalized treatment strategies, addressing a critical gap in patient care.

Researchers cross-sectionally evaluated 67 carriers (21 presymptomatic, 46 symptomatic) of pathogenic FTD mutations in GRN (n=30 symptomatic) and C9orf72 (n=16 symptomatic) genes, alongside 42 matched non-carriers. Clinical severity was assessed using the CDR plus NACC FTLD instrument. A panel of 124 CNS-related proteins was measured in plasma using the NULISA CNS assay. Group-level changes were then analyzed using linear and non-linear regression models to identify biomarker candidates.

In both GRN- and C9orf72-FTD, neurofilament light (NfL) was the most significantly altered protein compared to non-carriers. For GRN-FTD, NfL showed a β [95% CI] = 4.0 standard deviations [3.6-4.4], and for C9orf72-FTD, β = 2.8 [2.2-3.4]. Neurofilament heavy (NfH) was also notably altered, with GRN: β = 0.83 [0.39-1.3] and C9orf72: β = 1.4 [0.8-2.0]. Distinct protein changes were observed between the genetic subtypes:

Glial fibrillary acidic protein (GFAp; β = 0.50 [0.20-0.81]) and vascular cell adhesion protein 1 (VCAM1; Standardized β = -0.90 [-1.4 to -0.38]) were exclusively altered in GRN-FTD, changing with increasing disease severity. Neuronal pentraxin receptor (NPTXR; β = -0.94 [-1.5 to -0.4]) was selectively reduced in C9orf72-FTD. Additionally, several inflammatory mediators showed nominal changes in C9orf72-FTD.