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Early microglial and astrocyte reactivity in preclinical Alzheimer's disease
Fernández-Matarrubia M, Valera-Barrero A, Renuncio-García M, Aguilella M, Lage C, López-García S, Ocejo-Vinyals JG, Martínez-Dubarbie F et al.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025-08-01
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
Introduction The role of neuroinflammation in preclinical Alzheimer's disease (AD) remains unclear. Methods We assessed changes in microglial and astrocytic biomarkers in a well-characterized cohort of 211 cognitively unimpaired individuals. Structural equation modeling was used to simultaneously assess all relationships among microglial and astrocytic responses and AD pathological events. Results Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD. Plasma GFAP showed an inverse bidirectional relationship with CSF amyloid beta (Aβ)42/40. CSF sTREM2 directly influenced CSF phosphorylated tau-181 (p-tau181) and neurogranin, and correlated with CSF S100 calcium-binding protein beta (S100β). CSF chitinase-3-like protein 1 (YKL-40) mediated the association between CSF p-tau181 and total tau (t-tau), whereas CSF S100β and neurofilament light showed mutual influence. Discussion Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL-40 and S100β contribute to the progression of downstream neurodegenerative changes. Highlights Preclinical Alzheimer's disease (AD) showed increased levels of plasma glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) compared to cerebrospinal fluid (CSF) in healthy subjects. Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (Aβ)42/Aβ40. Higher CSF sTREM2 concentrations increased CSF phosphorylated tau-181. Chitinase-3-like protein 1 (YKL-40) mediated tau-induced neurodegeneration. S100 calcium-binding protein beta (S100β) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.
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APA 7th
Fernández-Matarrubia, M., Valera-Barrero, A., Renuncio-García, M., Aguilella, M., Lage, C., López-García, S., et al. (2025). Early microglial and astrocyte reactivity in preclinical Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.70502
Vancouver
Fernández-Matarrubia M, Valera-Barrero A, Renuncio-García M, Aguilella M, Lage C, López-García S, et al. Early microglial and astrocyte reactivity in preclinical Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2025. doi:10.1002/alz.70502. PMID: 40747577.
BibTeX
@article{fernandezmatarrubia2025-40747577,
author = {Fernández-Matarrubia, M. and Valera-Barrero, A. and Renuncio-García, M. and Aguilella, M. and Lage, C. and López-García, S. and Ocejo-Vinyals, J. G. and Martínez-Dubarbie, F. and others},
title = {{Early microglial and astrocyte reactivity in preclinical Alzheimer's disease}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2025},
doi = {10.1002/alz.70502},
pmid = {40747577},
url = {https://doi.org/10.1002/alz.70502}
}
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Key findings
- Results Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD.
- Discussion Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum.
- Highlights Preclinical Alzheimer's disease (AD) showed increased levels of plasma glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) compared to cerebrospinal fluid (CSF) in healthy subjects.
- Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (Aβ)42/Aβ40.
Why it matters
In 211 cognitively unimpaired people, plasma GFAP and CSF sTREM2 were increased in preclinical Alzheimer's disease, and the findings suggest microglial and astrocyte reactivity occurs early and affects the amyloid cascade. This is about early biomarker changes, not about treating, curing or preventing the disease.
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Study details
- Evidence strengthModerate
How this study scored 51/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia : the journal of the Alzheimer's Association) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| 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 | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 26 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 8.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 7.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 2 / 4 | Cited 26 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Eloy Rodríguez‐Rodríguez: h-index 41 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 22 institution(s) in 7 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40747577) |
| Free to read | 2 / 2 | Free to read |
| Total | 51 / 100 | — |
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