Serum GFAP captures cognitive vulnerability and Amyloid-Beta co-pathology across the ALS-FTD spectrum

Objectives To investigate whether glial fibrillary acidic protein (GFAP) reflects cognitive involvement across the amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD) spectrum, and to assess the impact of Amyloid-Beta co-pathology on FAP levels using AT biomarker classification. Material and methods We performed a cross-sectional analysis including 196 ALS patients, 13 PTD patients, and 44 healthy controls. Within the ALS cohort, patients were stratified according to Strong cognitive-behavioral categories and, in a biomarker-defined subgroup, according to cerebrospinal fluid (CSF) amyloid/tau status (A-T-, A+T-, A+T+). Serum and CSF GPAP and NfL were measured using ultrasensitive single molecule array and analyzed across diagnostic and phenotypic groups. Associations with clinical and cognitive variables were explored. Results Serum GAP differed significantly across diagnostic groups, with the highest levels in FTD compared with ALS and healthy controls (p=0.002), whereas CSF GAP did not differ significantly between ALS and FTD. Within ALS, serum GFAP increased across the cognitive spectrum and was highest in ALS-FTD, with significant differences versus ALScn (p=0.004) and ALSbi (p=0.047). By contrast, serum NfL did not significantly distinguish cognitive phenotypes across Strong categories (p=0.383), supporting a closer relationship of GFAP with cognitive-behavioral involvement. Serum GFAP was associated with older age, greater functional disability, worse global and ALS-specific cognitive performance, and higher serum NfL. When ALS patients were stratified according to AT status, serum GFAP progressively increased from A-T- to A+T- and A+T+, reaching the highest values in A+T+ cases (global p=0.017; A+T+ vs A-T-p=0.035). Conclusion Serum GFAP captures clinically relevant cognitive vulnerability within the ALS-FTD continuum and appears to discriminate ALS cognitive phenotypes better than NfL. Its marked increase in A+T+ ALS further suggests that Amyloid-Beta co-pathology substantially influences GAP levels and may contribute to the cognitive phenotype.