Plasma GFAP as a mediator and moderator of Aβ, tau, and neurodegeneration in Alzheimer’s disease

Astrogliosis is increasingly recognized as a critical component of Alzheimer's disease (AD) pathology, but its precise mechanistic contribution to the interplay among amyloid-β (Aβ), tau, and neurodegeneration remains unclear. Glial fibrillary acidic protein (GFAP), a widely used biomarker of astrocytic activation, shows strong associations with both Aβ and tau pathologies; however, its causal and modulatory involvement in disease progression has yet to be fully delineated. In this study, we investigated whether plasma GFAP functions as a mediator and/or moderator of the relationships linking Aβ deposition, tau accumulation, and neurodegenerative changes in AD. Ninety-two older adults from the KBASE cohort underwent multimodal imaging including Aβ-PET, tau-PET, FDG-PET, and MRI-based hippocampal volumetry, along with blood sampling for plasma GFAP assessment. Elevated plasma GFAP levels were associated with increased Aβ and tau burden, reduced cerebral glucose metabolism, and smaller hippocampal volume, as well as poorer cognitive performance. Mediation analyses demonstrated that GFAP significantly explained the relationships between Aβ and tau, and between tau and metabolic dysfunction. Moderation analyses further revealed that GFAP strengthened the Aβ-tau association, while mitigating tau-related metabolic decline. Overall, these results support a dual role of GFAP as both a conduit and regulator of disease progression.

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Publication Details

Journal
npj Dementia
Published
2026-01-09
DOI
https://doi.org/10.1038/s44400-025-00051-x
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

Plasma GFAP as a mediator and moderator of Aβ, tau, and neurodegeneration in Alzheimer’s disease

Y. Kim, Bo Kyung Sohn, Jee-Eun Park, Joon Choi et al.
npj Dementia
Alzheimer's disease research and treatments
article

Plasma GFAP as a mediator and moderator of Aβ, tau, and neurodegeneration in Alzheimer’s disease

Y. Kim, Bo Kyung Sohn, Jee-Eun Park, Joon Choi, M. Kim, Hyejin Ahn, S. Kim, Juneyoung Lee, HyeJi Choi, Dohyun Woo, Dahyun Yi, Min Soo Byun, Jun Sung Kim, Koung Mi Kang, Dong Kyun Han, Woo Jin Kim, Yun-Sang Lee, Gijung Jung, Chul-Ho Sohn, Dong Young Lee, Donghee Kim, Seung Min Han
article en

Abstract

Astrogliosis is increasingly recognized as a critical component of Alzheimer's disease (AD) pathology, but its precise mechanistic contribution to the interplay among amyloid-β (Aβ), tau, and neurodegeneration remains unclear. Glial fibrillary acidic protein (GFAP), a widely used biomarker of astrocytic activation, shows strong associations with both Aβ and tau pathologies; however, its causal and modulatory involvement in disease progression has yet to be fully delineated. In this study, we investigated whether plasma GFAP functions as a mediator and/or moderator of the relationships linking Aβ deposition, tau accumulation, and neurodegenerative changes in AD. Ninety-two older adults from the KBASE cohort underwent multimodal imaging including Aβ-PET, tau-PET, FDG-PET, and MRI-based hippocampal volumetry, along with blood sampling for plasma GFAP assessment. Elevated plasma GFAP levels were associated with increased Aβ and tau burden, reduced cerebral glucose metabolism, and smaller hippocampal volume, as well as poorer cognitive performance. Mediation analyses demonstrated that GFAP significantly explained the relationships between Aβ and tau, and between tau and metabolic dysfunction. Moderation analyses further revealed that GFAP strengthened the Aβ-tau association, while mitigating tau-related metabolic decline. Overall, these results support a dual role of GFAP as both a conduit and regulator of disease progression.

npj DementiaVol. 2(1)
Seoul National University (KR), Konkuk University (KR), Soonchunhyang University (KR), Soonchunhyang University Hospital Seoul (KR), Seoul National University Hospital (KR), Seoul National University Bundang Hospital (KR), Genome and Company (South Korea) (KR), SNUH SMG-SNU Boramae Medical Center (KR), Korea Institute of Materials Science (KR), Kangwon National University Hospital (KR), Inje University Sanggye Paik Hospital (KR), National Health Insurance Service Ilsan Hospital (KR), Chungnam National University Hospital (KR), Myongji Hospital (KR), Hallym University Dongtan Sacred Heart Hospital (KR), National Health Insurance Service (KR), Chungbuk National University Hospital (KR), Keimyung University (KR), Bucheon University (KR), Chung-Ang University (KR)
National Research Foundation, Seoul National University, Korea Health Industry Development Institute, National Research Foundation of Korea, Ministry of Science and ICT, South Korea, Avid Radiopharmaceuticals
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Alzheimer's disease research and treatments
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