GFAP: An Emerging Biomarker for Neurodegeneration and Astrocyte Function

For many years, research on neurodegenerative diseases focused primarily on neurons. Today, we know that astrocytes also play an important role in brain function. Astrocytes are a type of glial cell that supports neurons and, among other functions, regulates the cellular environment, maintains the blood-brain barrier, and coordinates the brain’s response to injury and inflammation.

When the nervous system is affected by injury or other pathological changes, astrocytes can alter their morphology and activity, a process known as reactive astrogliosis. This response may initially play a protective role by helping limit damage and restore homeostasis. However, when it is prolonged or dysregulated, it may contribute to persistent neuroinflammation and changes in the neural environment associated with neurodegeneration.

One biomarker that can reflect this astrocytic response is GFAP (Glial Fibrillary Acidic Protein), a cytoskeletal protein expressed primarily in astrocytes. The ability to measure very low concentrations of GFAP in the blood has increased interest in studying it in Alzheimer’s disease, multiple sclerosis, and other neurological disorders.

What Is GFAP?

GFAP belongs to the family of intermediate filament proteins, which are key structural components of the cytoskeleton. It is expressed primarily in central nervous system astrocytes and helps maintain their structure and organization.

Under normal conditions, astrocytes actively contribute to brain homeostasis. However, when injury, inflammation, or another pathological change occurs, they can alter their gene expression, morphology, and functional state. Increased GFAP expression is frequently observed as part of this reactive response. For this reason, GFAP is regarded primarily as a biomarker of astrocyte reactivity and injury rather than a direct measure of all astrocyte functions.

GFAP and Alzheimer’s Disease

The strongest research evidence to date for GFAP as a blood-based biomarker relates to Alzheimer’s disease.

Studies have shown that blood GFAP levels are, on average, higher in individuals with Alzheimer’s disease and mild cognitive impairment than in cognitively healthy groups. A 2024 systematic review and meta-analysis that included 36 studies and more than 7,000 participants in total found significantly higher blood GFAP concentrations across the Alzheimer’s disease spectrum.

GFAP is of particular interest as a marker of astrocyte response during the progression of Alzheimer’s disease. Studies of individuals with rare inherited forms of the disease have shown that blood GFAP may begin to increase several years before symptom onset. These findings suggest that the astrocytic response may represent an early component of the disease's pathophysiological course and that GFAP may provide information about this aspect of the disease process.

GFAP Beyond Alzheimer’s Disease

Beyond Alzheimer’s Disease, interest in GFAP is also increasing when it comes to:

1. Multiple Sclerosis

In multiple sclerosis, particularly in progressive forms, researchers are investigating whether GFAP can provide information that differs from that provided by NfL (Neurofilament Light Chain).

NfL more closely reflects neuroaxonal injury, whereas GFAP is more strongly associated with the astroglial response. Recent studies suggest that elevated serum GFAP concentrations may be associated with disability progression, including progression occurring independently of relapses.

2. Parkinson’s Disease and Other Neurodegenerative Disorders

GFAP is also being studied in Parkinson’s disease and atypical parkinsonian syndromes. Some studies have associated higher levels with specific clinical characteristics or disease progression. However, the findings are not yet sufficiently consistent for GFAP to be considered an established independent biomarker for Parkinson’s disease.

Similar research is also being conducted in other conditions, such as amyotrophic lateral sclerosis, although specificity remains insufficient to support widespread standalone diagnostic use.

GFAP Does Not Necessarily Indicate Neurodegeneration

GFAP is not specific to any particular neurodegenerative disease. Elevated concentrations can occur with substantial astrocyte activation or injury from different causes.

GFAP has been studied, among other conditions, in traumatic brain injury and stroke. In acute stroke, its use is being investigated in an entirely different clinical context, such as the rapid differentiation of intracerebral hemorrhage from ischemia.

Therefore, a change in GFAP should not automatically be interpreted as meaning that “a neurodegenerative disease is present.” Age and other biological factors can also influence its concentrations.

GFAP, NfL, Amyloid, and Tau: Different Biomarkers Provide Different Information

Modern research increasingly focuses on biomarker combinations rather than a single test that can answer every question. Different biomarkers can reflect different biological processes:

• GFAP: primarily associated with astrocyte reactivity and astrogliosis.
• NfL: a marker of neuroaxonal injury, without being specific to any single disease.
• p-tau181 and p-tau217: phosphorylated forms of tau that are more closely associated with the pathophysiology of Alzheimer’s disease.
• Aβ1-40 and Aβ1-42: beta-amyloid biomarkers that provide information related to amyloid pathology and are evaluated within the appropriate clinical context alongside other biomarkers.
   

The aim, therefore, is not necessarily to identify the “best” biomarker, but to understand which biological process each biomarker reflects and how to combine this information with medical history, neurological and cognitive assessment, and, where indicated, imaging.

Conclusion

GFAP is an important emerging biomarker in modern neurobiology, as it provides information about astrocyte reactivity and highlights the role of astrocytes in pathological processes affecting the nervous system. A substantial body of evidence now shows that blood concentrations are associated with biological changes in the central nervous system. Particularly in Alzheimer’s disease, the relationship between elevated GFAP, amyloid pathology, and disease progression is supported by a growing number of studies, while research is expanding into multiple sclerosis, Parkinson’s disease, and other neurological conditions.

However, GFAP is not specific to any single disease, and an elevated value does not diagnose neurodegeneration. Astrocyte reactivity represents only one dimension of a complex biological system that also involves neurons, microglia, blood vessels, and metabolic and immune mechanisms. For this reason, GFAP's value appears to lie primarily in its assessment within the appropriate clinical context and, where indicated, in combination with other biomarkers and imaging findings.

As our understanding of neurological biomarkers continues to evolve, assessing different biological processes may contribute to a more comprehensive picture of nervous system health. GFAP is a characteristic example of this development, highlighting how modern laboratory investigation can provide information beyond traditional biomarkers and support a more personalized approach to health assessment.

References

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