Related Experiment Video
Updated: Aug 5, 2026
Experimental Approaches for Biochemical Analysis of Glial Fibrillary Acidic Protein and Its Disease-associated Variants
Published on: November 28, 2025
Serum Glial Fibrillary Acidic Protein Dynamics, Disease Progression, and Therapy Response in Multiple Sclerosis
Maximilian Einsiedler1, Sofia Sandgren1, Sabine Schaedelin1
1Multiple Sclerosis Center and Research Center for Clinical Neuroimmunology and Neuroscience, Neurology Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
Importance:
Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation.
Objective:
To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA).
Design, Setting, And Participants:
This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements).
Exposures:
Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months.
Main Outcomes And Measures:
Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC).
Results:
The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively.
Conclusions And Relevance:
In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.
Insights
Elevated glial fibrillary acidic protein (GFAP) indicates higher multiple sclerosis progression risk, while decreasing levels signal lower risk. GFAP shows promise as a biomarker for personalized risk assessment and clinical trial screening.
Area of Science:
- Neuroimmunology
- Biomarker Discovery
- Clinical Neurology
Background:
- Multiple sclerosis (MS) progression is challenging to track individually.
- Glial fibrillary acidic protein (GFAP) has potential as a biomarker, but requires validation in large longitudinal studies.
- Few studies have assessed GFAP's association with progression independent of relapse activity (PIRA).
Purpose of the Study:
- To determine if serum GFAP levels and treatment-induced changes correlate with future PIRA.
- To evaluate GFAP as a potential biomarker for risk stratification and treatment monitoring in MS.
- To assess GFAP's utility in optimizing clinical trial design for MS progression.
Main Methods:
- Prospective observational study utilizing two large MS cohorts (Swiss MS Cohort and EPIC).
- Included 2329 persons with MS with longitudinal neurofilament light chain (NfL) and GFAP measurements.
- Analyzed clinical data and GFAP/NfL z-scores collected every 6-12 months.
Main Results:
- Elevated GFAP levels were associated with a significantly higher risk of future PIRA (Hazard Ratios ranging from 1.36 to 1.45).
- Reductions in GFAP levels during treatment with fingolimod or B-cell-depleting therapies correlated with a substantially lower risk of subsequent PIRA (54% and 67% risk reductions, respectively).
- GFAP could potentially reduce clinical trial sample sizes by approximately 20% when used for cohort enrichment.
Conclusions:
- Serum GFAP is a valuable biomarker for predicting PIRA risk in multiple sclerosis.
- Treatment-induced changes in GFAP levels reflect treatment efficacy and correlate with reduced PIRA risk.
- GFAP can aid in personalized risk stratification, treatment monitoring, and enhancing the efficiency of clinical trials for MS progression.
