The Role of Glial Fibrillary Acidic Protein in the Neuropathology of Alzheimer's Disease and Its Potential as a Blood Biomarker for Early Diagnosis and Progression

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterised by neuropathological hallmarks, including extracellular amyloid plaques and neurofibrillary tangles. The disease is clinically defined by cognitive dysfunction, including learning, memory deficits, and behavioural changes. With the rising global prevalence of AD, early diagnosis is critical for implementing effective interventions before irreversible neuronal damage occurs. Biomarkers correlating amyloid deposition, tau pathology, neuroinflammation, and neurodegeneration are currently being investigated using cerebrospinal fluid analysis and positron emission tomography imaging. These methods are invasive or costly, limiting their widespread clinical utility. Blood-based biomarkers offer a promising alternative due to accessibility, cost-effectiveness, and feasibility for large-scale screening. Among blood-based biomarkers, plasma glial fibrillary acidic protein (GFAP) levels have gained interest in identifying individuals at risk of AD at preclinical stages. However, significant challenges remain, including methodological inconsistencies, analytical variability, and the need for standardisation across immunoassay platforms to ensure the clinical applicability of plasma GFAP measurement in AD diagnosis. Additionally, the specificity of GFAP for AD needs further evaluation, as increased plasma levels are also observed in other diseases. Similar issues are found with p-tau 217, the blood biomarker candidate for AD that has received the most attention. This review summarises the role of GFAP in the neuropathology of AD, provides evidence on plasma GFAP as an early blood biomarker for AD and identifies key knowledge gaps that need to be addressed. Future advancements in assay development and large-scale longitudinal studies are essential to validate its diagnostic and prognostic potential for community-based AD screening.

Keywords: AD; Alzheimer’s disease; Blood biomarkers; GFAP; GFAP isoforms; Glial fibrillary acidic protein.