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Reframing TDP-43 in Alzheimer's disease: From co-pathology to neurovascular culprit
Martina Gaia Di Donna, Caterina Motta, Chiara Giuseppina Bonomi, Francesca Bernocchi, Francesco Ricci, Martina Poli, Giacomo Koch, Alessandro Martorana. Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025-12
Topic: Inflammation, microglia and astrocytes
Alzheimer's disease (AD) is widely recognized as a multifactorial disorder involving neurovascular and glial dysfunction beyond amyloid-β and tau pathology. In this Perspective, we synthesize recent evidence to propose a conceptual framework linking transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) to neurovascular unit (NVU) disruption in AD. Traditionally considered a neuronal co-pathology, TDP-43 also aggregates in astrocytes and endothelial cells, impairing blood-brain barrier (BBB) integrity, glymphatic clearance, and metabolic homeostasis. Endothelial TDP-43 loss disrupts β-catenin signaling and fibronectin, triggering vascular breakdown and neuroinflammation. Astrocytic perivascular aggregates correlate with reduced aquaporin-4 (AQP4) and CD146, further compromising clearance pathways. These vascular-glial mechanisms may accelerate AD progression and help explain clinical heterogeneity and limited therapeutic response in TDP-43-positive patients. We argue for the reclassification of TDP-43 as a potential upstream driver of disease progression. Such a shift would support the development of integrative biomarkers and precision treatment strategies targeting NVU dysfunction. HIGHLIGHTS: Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) may act as a driver of neurovascular dysfunction in Alzheimer's disease (AD). We propose reclassifying TDP-43 from co-pathology to upstream contributor. TDP-43 affects endothelial cells and astrocytes, disrupting blood-brain barrier (BBB) and clearance. Neurovascular unit (NVU) dysfunction links TDP-43 to inflammation, hypoperfusion, and cognitive decline. A vascular-glial model of AD opens new therapeutic and biomarker opportunities.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Di Donna, M. G., Motta, C., Bonomi, C. G., Bernocchi, F., Ricci, F., Poli, M., et al. (2025). Reframing TDP-43 in Alzheimer's disease: From co-pathology to neurovascular culprit. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.70988
Vancouver
Di Donna MG, Motta C, Bonomi CG, Bernocchi F, Ricci F, Poli M, et al. Reframing TDP-43 in Alzheimer's disease: From co-pathology to neurovascular culprit. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2025. doi:10.1002/alz.70988. PMID: 41399037.
BibTeX
@article{didonna2025-41399037,
author = {Di Donna, Martina Gaia and Motta, Caterina and Bonomi, Chiara Giuseppina and Bernocchi, Francesca and Ricci, Francesco and Poli, Martina and Koch, Giacomo and Martorana, Alessandro},
title = {{Reframing TDP-43 in Alzheimer's disease: From co-pathology to neurovascular culprit}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2025},
doi = {10.1002/alz.70988},
pmid = {41399037},
url = {https://doi.org/10.1002/alz.70988}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- HIGHLIGHTS: Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) may act as a driver of neurovascular dysfunction in Alzheimer's disease (AD).
- We propose reclassifying TDP-43 from co-pathology to upstream contributor.
- TDP-43 affects endothelial cells and astrocytes, disrupting blood-brain barrier (BBB) and clearance.
- Neurovascular unit (NVU) dysfunction links TDP-43 to inflammation, hypoperfusion, and cognitive decline.
- A vascular-glial model of AD opens new therapeutic and biomarker opportunities.
Study details
- Evidence strengthLow
How this study scored 46/100
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. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multicenter collaboration and free to read, so those were left out: it earned 26 of the 56 points we could judge it on, which is 46 out of 100.
| 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 | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (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 | 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41399037) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 26 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 26 of the 56 points we could judge it on is 46 out of 100. |
| Total | 46 / 100 | — |
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