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Interplay between astrocyte reactivity and APOE ε4 status is associated with accelerated pTau-related tau pathology in Alzheimer's disease
Mao X, Wang Y, Luan Y, Wang Y, Wang J, Dai W, Guan Y, Huang Q, Gunn RN, Ossenkoppele R, Li B, Li Z, et al.. Molecular Neurodegeneration, 2025-10-29
Topic: Brain proteins, microglia and lab models
Plasma GFAP and pTau biomarkers (pTau181, pTau231, pTau217) are significantly elevated in Aβ-positive individuals, with stronger Aβ–pTau associations observed in APOE ε4 carriers (CPAS: β = 0.26, p = 0.003 for pTau231; ADNI: β = 0.45, p < 0.001 for pTau181). Across two cohorts, plasma GFAP levels significantly strengthened the associations between pTau biomarkers and Tau PET. Furthermore, subsequent analyses revealed that this modulatory effect of GFAP on the links between pTau and PET-derived pathological changes was more pronounced in APOE ε4 non-carriers, whereas in APOE ε4 carriers, a significant interaction between GFAP and pTau was only observed in specific Braak stage-specific regions within the CPAS cohort. In longitudinal analyses, we also observed stronger pTau181-associated longitudinal tau accumulation in individuals with high GFAP levels (Braak III-IV). We demonstrate that APOE ε4 status critically modulates the relationship between pTau and Aβ pathology, whereas plasma GFAP primarily influences pTau–tau pathology associations, particularly in individuals without APOE ε4 allele. These findings underscore the role of reactive astrogliosis in tau propagation and support the utility of plasma biomarkers for AD diagnosis and prognosis.
Key findings
- Plasma GFAP and pTau biomarkers (pTau181, pTau231, pTau217) are significantly elevated in Aβ-positive individuals, with stronger Aβ–pTau associations observed in APOE ε4 carriers (CPAS: β = 0.26, p = 0.003 for pTau231; ADNI: β = 0.45, p < 0.001 for pTau181).
- Across two cohorts, plasma GFAP levels significantly strengthened the associations between pTau biomarkers and Tau PET.
- Furthermore, subsequent analyses revealed that this modulatory effect of GFAP on the links between pTau and PET-derived pathological changes was more pronounced in APOE ε4 non-carriers, whereas in APOE ε4 carriers, a significant interaction between GFAP and pTau was only observed in specific Braak stage-specific regions within the CPAS cohort.
- In longitudinal analyses, we also observed stronger pTau181-associated longitudinal tau accumulation in individuals with high GFAP levels (Braak III-IV).
- We demonstrate that APOE ε4 status critically modulates the relationship between pTau and Aβ pathology, whereas plasma GFAP primarily influences pTau–tau pathology associations, particularly in individuals without APOE ε4 allele.
Why it matters
Across two cohorts, plasma GFAP strengthened the associations between pTau biomarkers and Tau PET, with this modulatory effect more pronounced in APOE ε4 non-carriers, and longitudinal analyses showed stronger pTau181-associated tau accumulation in people with high GFAP. The work supports the use of plasma biomarkers for diagnosis and prognosis and highlights reactive astrogliosis in tau propagation, but does not test a treatment.
Study details
- Study designcohort
- Participants806
- Effect sizeAmyloid-p-tau association beta = 0.26 (CPAS) and 0.45 (ADNI) in APOE e4 carriers
- Evidence strengthModerate
Limitations
Insufficient longitudinal follow-up in the CPAS cohort and a small ADNI longitudinal sample (n = 101) prevented verification of interactions over time; cohort differences in ethnicity, education, assay platforms and PET pipelines may explain inconsistencies for specific p-tau isoforms; and plasma GFAP is sensitive but not specific to astrocyte activation.
How this study scored 59/100
Published in a peer-reviewed journal, and it is a cohort study following people over time. Scored zero for randomised / blinded because the record does not state it. We have no data on senior author's track record and free to read, so those were left out: it earned 55 of the 94 points we could judge it on, which is 59 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular Neurodegeneration) |
| Journal's citation record | 2 / 4 | Molecular Neurodegeneration: journal h-index 164 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 806 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 6 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 2 / 3 | Imperial College London: institution h-index 1,744 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 15 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41163175) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 55 / 94 | Scored on 18 of 20 parts. We have no data for the rest, so they are left out: 55 of the 94 points we could judge it on is 59 out of 100. |
| Total | 59 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Mao, X., Wang, Y., Luan, Y., Wang, J., Dai, W., Guan, Y., et al. (2025). Interplay between astrocyte reactivity and APOE ε4 status is associated with accelerated pTau-related tau pathology in Alzheimer's disease. Molecular Neurodegeneration. https://doi.org/10.1186/s13024-025-00906-0
Vancouver
Mao X, Wang Y, Luan Y, Wang J, Dai W, Guan Y, et al. Interplay between astrocyte reactivity and APOE ε4 status is associated with accelerated pTau-related tau pathology in Alzheimer's disease. Molecular Neurodegeneration. 2025. doi:10.1186/s13024-025-00906-0. PMID: 41163175.
BibTeX
@article{mao2025-41163175,
author = {Mao, X. and Wang, Y. and Luan, Y. and Wang, J. and Dai, W. and Guan, Y. and Huang, Q. and Gunn, R. N. and Ossenkoppele, R. and Li, B. and Li, Z. and others},
title = {{Interplay between astrocyte reactivity and APOE ε4 status is associated with accelerated pTau-related tau pathology in Alzheimer's disease}},
journal = {Molecular Neurodegeneration},
year = {2025},
doi = {10.1186/s13024-025-00906-0},
pmid = {41163175},
url = {https://doi.org/10.1186/s13024-025-00906-0}
}
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