Entorhinal cortex astrocytes in early Alzheimer disease: Human evidence, cross-species circuit rationale, and translational boundaries
Fengjuan Wu, Manxia Wang. Journal of Neuropathology & Experimental Neurology, 2026-08-18
Topic: Brain proteins, microglia and lab models
Alzheimer disease (AD) pathology affects the transentorhinal/entorhinal region early but whether entorhinal cortex (EC) astrocytes are causal drivers or therapeutic targets remains unresolved. This narrative review evaluates EC astrocytes through an explicit evidence hierarchy. We distinguish: (1) human EC-specific neuropathology, imaging, and transcriptomic findings, (2) human AD astrocyte data lacking EC-cell resolution, (3) mechanistic evidence from animal and cellular models, and (4) translational hypotheses. Human data support early EC vulnerability and region- and stage-dependent astrocyte remodeling, whereas the most direct functional evidence comes from rodent medial EC layer II and should be interpreted as circuit plausibility rather than anatomical equivalence to the human EC. We therefore prioritize candidate astrocyte modules according to astrocyte specificity, relevance to EC or medial temporal pathology, mechanistic links to circuit dysfunction, and the availability of measurable target-engagement readouts. These modules include inflammatory-complement signaling, EAAT2/GLT-1-mediated glutamate clearance, MAO-B/GABA metabolism, AQP4-related gliovascular regulation, astrocytic calcium signaling, and APOE-related lipid handling. Cell transplantation, glial reprogramming, and engineered extracellular vesicles remain experimental platforms. EC astrocytes should therefore be viewed as candidate circuit-glial vulnerability nodes requiring human validation, not as established clinical targets.
Key findings
- Human data support early EC vulnerability and region- and stage-dependent astrocyte remodeling, whereas the most direct functional evidence comes from rodent medial EC layer II and should be interpreted as circuit plausibility rather than anatomical equivalence to the human EC.
- We therefore prioritize candidate astrocyte modules according to astrocyte specificity, relevance to EC or medial temporal pathology, mechanistic links to circuit dysfunction, and the availability of measurable target-engagement readouts.
- These modules include inflammatory-complement signaling, EAAT2/GLT-1-mediated glutamate clearance, MAO-B/GABA metabolism, AQP4-related gliovascular regulation, astrocytic calcium signaling, and APOE-related lipid handling.
- Cell transplantation, glial reprogramming, and engineered extracellular vesicles remain experimental platforms.
- EC astrocytes should therefore be viewed as candidate circuit-glial vulnerability nodes requiring human validation, not as established clinical targets.
Why it matters
This review examines evidence on entorhinal cortex astrocytes in early Alzheimer's disease and concludes that whether they are causal drivers or therapeutic targets remains unresolved. It prioritizes candidate astrocyte modules for future study, but the most direct functional evidence comes from rodents and is described as circuit plausibility rather than proof in humans.
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Study details
- Study designnarrative review
- Evidence strengthLow
How this study scored 28/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Neuropathology & Experimental Neurology) |
| Journal's citation record | 2 / 4 | Journal of Neuropathology & Experimental Neurology: journal h-index 239 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | Design recorded as “narrative review”, which our rubric does not rank (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 0 / 6 | Cited 0.0× 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 | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Manxia Wang: h-index 17 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Lanzhou University Second Hospital: institution h-index 151 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 42700370) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 28 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Wu, F., & Wang, M. (2026). Entorhinal cortex astrocytes in early Alzheimer disease: Human evidence, cross-species circuit rationale, and translational boundaries. Journal of Neuropathology & Experimental Neurology. https://doi.org/10.1093/jnen/nlag098
Vancouver
Wu F, Wang M. Entorhinal cortex astrocytes in early Alzheimer disease: Human evidence, cross-species circuit rationale, and translational boundaries. Journal of Neuropathology & Experimental Neurology. 2026. doi:10.1093/jnen/nlag098. PMID: 42700370.
BibTeX
@article{wu2026-42700370,
author = {Wu, Fengjuan and Wang, Manxia},
title = {{Entorhinal cortex astrocytes in early Alzheimer disease: Human evidence, cross-species circuit rationale, and translational boundaries}},
journal = {Journal of Neuropathology \& Experimental Neurology},
year = {2026},
doi = {10.1093/jnen/nlag098},
pmid = {42700370},
url = {https://doi.org/10.1093/jnen/nlag098}
}
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