Glial fibrillary acidic protein (GFAP) in biofluids: analytical considerations and clinical relevance in neurodegenerative diseases.

For many years, astrocytes were viewed mainly as supportive cells, responding passively to neuronal injury. Over the last decade, this perspective has changed substantially, and astrocytes are now shown to be highly dynamic cells that actively shape neurodegenerative processes. As a result, interest has grown in biomarkers capable of capturing astrocytic activity in vivo. Glial fibrillary acidic protein (GFAP), an intermediate filament protein predominantly expressed by astrocytes, is released into cerebrospinal fluid and blood during astrogliosis and can be reliably measured using ultrasensitive immunoassays. Increasing evidence indicates that GFAP levels are elevated across several neurodegenerative diseases and reflect both disease presence and severity. In Alzheimer's disease, blood GFAP rises early in the disease course, often before overt cognitive decline, and is closely associated with amyloid pathology and subsequent progression. In Lewy body dementia and Parkinson's disease, GFAP provides complementary information by reflecting astroglial activation, identifying patients with concomitant Alzheimer's pathology, and capturing disease heterogeneity. In frontotemporal dementia, GFAP levels are consistently increased and correlate with disease severity, particularly in genetic forms, although disease specificity remains limited. Beyond its diagnostic value, GFAP holds promise as a prognostic and pharmacodynamic biomarker, supporting patient stratification and monitoring in clinical trials. However, its clinical interpretation requires careful consideration of analytical methods, pre-analytical conditions, age-related effects, and systemic confounders. Overall, GFAP has emerged as a valuable marker of astrocytic involvement in neurodegeneration and represents an important component of future multimodal biomarker strategies aimed at improving precision medicine in neurology.