Age-Specific Control and Alzheimer Disease Reference Curves and z-Scores for Glial Fibrillary Acidic Protein in Blood

Background Serum glial fibrillary acidic protein (GFAP) is a biomarker for astrocytic injury and astrogliosis. Concentrations are elevated in numerous neurological disorders, including a pronounced increase in Alzheimer disease (AD). However, GFAP levels in the serum also increase with age. Consequently, the integration of GFAP levels into clinical routine and their interpretation demands age-adjusted reference values. Methods Serum from 1273 subjects (952 noninflammatory and nonneurodegenerative neurological controls and 321 subjects with AD) was analyzed for GFAP using the microfluidic Ella system. Age-dependent serum GFAP reference values were estimated by additive quantile regression analysis and visualized with percentiles and z-scores. Results AD exhibited elevated serum GFAP levels in comparison to control patients (P < 0.0001). This remained the case when the newly generated age-corrected z-scores were applied (P < 0.0001). In the control cohort, a nonlinear elevation of serum GFAP with increasing age was observed (Spearman correlation coefficient 0.62, 95% CI 0.58–0.66, P < 0.0001). In contrast, the AD cohort exhibited a more linear increase (0.16, 95% CI 0.05–0.26, P = 0.004). Age-dependent cut-offs for serum GFAP were determined for different AD age groups. The calculated areas under the curve (AUCs; 0.97) demonstrated excellent diagnostic test performance in the early-onset age group. This effect was less marked in the elderly subjects (AUC 0.72). Conclusions Our novel GFAP z-scores enable the integration and interpretation of serum GFAP levels in clinical practice, moving from the group to individual level. They support both intra- and interindividual interpretation of single GFAP levels in neurological diseases with astrocytic pathology, including an accurate discrimination of AD.