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APOE4 reduction in vascular-associated fibroblasts decreases cerebral amyloid angiopathy and associated vascular dysfunction
Saadi F, Cho Y, Katritch IV, Lugo B, Wu Y, Smyth LC, Bosch M, Telfer KA et al.. bioRxiv, 2026-10-04
Topic: Inflammation, microglia and astrocytes
Cerebral amyloid angiopathy (CAA), characterized by cerebrovascular amyloid deposition, is strongly associated with Alzheimer’s disease, ischemic injury, and lobar hemorrhages. APOE4 is the strongest known genetic risk factor for CAA, yet the cellular sources of APOE4 that drive pathogenic vascular amyloid deposition remain poorly defined. Here, we identify vascular-associated fibroblasts (VAFs) as a key source of APOE4 that mediates CAA and cerebrovascular dysfunction. In post-mortem brain tissue from APOE4/E4 patients with confirmed CAA, APOE colocalizes with COL6⁺ VAFs around Aβ-laden vessels. Therefore, to study the contribution of APOE4 derived from VAFs in CAA, independently of parenchymal sources, we used 5xFAD mice in which the endogenous mouse Apoe coding exons are replaced with floxed human APOE4 sequences. This enables selective suppression of APOE4 expression in VAFs upon tamoxifen induction of Col1a2-CreERT + . APOE4 reduction in VAFs markedly reduced CAA, with the strongest effects observed in leptomeningeal vessels. Additionally, Aβ40, which preferentially associates with vascular amyloid, was significantly reduced in the vascular fraction. VAF APOE4 depletion resulted in fewer small microbleeds and an approximately 50% reduction in parenchymal border macrophages within the leptomeningeal compartment, whereas astrocytic reactivity remained unchanged. Functional assessment using in vivo multi-parametric photoacoustic microscopy revealed improved arterial dilation and blood flow in amyloid-laden leptomeningeal arteries. Together, these findings establish VAF-derived APOE4 as a compartment-specific driver of CAA and cerebrovascular dysfunction. One Sentence Summary Vascular-associated fibroblasts are a major source of pathogenic APOE4 that drives vascular dysfunction in cerebral amyloid angiopathy.
Key findings
- Cerebral amyloid angiopathy (CAA), characterized by cerebrovascular amyloid deposition, is strongly associated with Alzheimer’s disease, ischemic injury, and lobar hemorrhages.
- Additionally, Aβ40, which preferentially associates with vascular amyloid, was significantly reduced in the vascular fraction.
- Functional assessment using in vivo multi-parametric photoacoustic microscopy revealed improved arterial dilation and blood flow in amyloid-laden leptomeningeal arteries.
- Together, these findings establish VAF-derived APOE4 as a compartment-specific driver of CAA and cerebrovascular dysfunction.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on 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 and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| 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 | — / 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 |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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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. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Saadi, F., Cho, Y., Katritch, IV., Lugo, B., Wu, Y., Smyth, L. C., et al. (2026). APOE4 reduction in vascular-associated fibroblasts decreases cerebral amyloid angiopathy and associated vascular dysfunction. bioRxiv. https://doi.org/10.64898/2026.10.02.756327
Vancouver
Saadi F, Cho Y, Katritch IV, Lugo B, Wu Y, Smyth LC, et al. APOE4 reduction in vascular-associated fibroblasts decreases cerebral amyloid angiopathy and associated vascular dysfunction. bioRxiv. 2026. doi:10.64898/2026.10.02.756327.
BibTeX
@article{saadi2026-e9af705a,
author = {Saadi, F. and Cho, Y. and Katritch, IV. and Lugo, B. and Wu, Y. and Smyth, L. C. and Bosch, M. and Telfer, K. A. and others},
title = {{APOE4 reduction in vascular-associated fibroblasts decreases cerebral amyloid angiopathy and associated vascular dysfunction}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.02.756327},
url = {https://doi.org/10.64898/2026.10.02.756327}
}
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