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A Quantitative Trait Locus for Reduced MicroglialAPOEExpression Associates with Reduced Cerebral Amyloid Angiopathy
Belloy ME, Graff-Radford J, Greicius MD.. medRxiv, 2025-03-13
Topic: Brain proteins, microglia and lab models
The Apolipoprotein E (APOE) e4 and e2 alleles are respectively the most risk increasing and risk decreasing, common genetic risk factors for Alzheimer’s disease (AD) 1,2 . They strongly affect Aβ burden in the brain parenchyma 1 , a core hallmark of AD, but also at the level of the brain vasculature, i.e. cerebral amyloid angiopathy (CAA) 1,3 , which in turn relates to increased risk for amyloid-related imaging abnormalities (ARIA) in APOE *4 carriers when receiving anti-Aβ antibody treatments 4 . This makes APOE a highly pursued AD drug target. A crucial question in the field is whether it would be beneficial to either increase or decrease APOE (particularly APOE *4) levels 5 . The answer from rodent work appears to converge on “decreasing APOE levels” 5–7 , with initial human studies supporting this 5,8,9 . Human genetic evidence however remains scarce and new insights are crucially needed to support clinical translation. Shade et al. 2024 conducted the largest to date genome-wide association study (GWAS) of various neuropathological traits, identifying a variant protective of CAA in the APOE locus independent of APOE *4 and APOE *2 genotypes 10 . Downstream analyses suggested this signal links to the nearby APOC2 gene through local effects on methylation. We applaud the authors on their timely, relevant, and well-conducted study. Here, we extend on these findings, highlighting there is compelling evidence that their genetic signal for reduced CAA relates to an effect on reduced microglial APOE expression, which would importantly support the evidence in favor of “decreasing APOE levels” and further herald this promising therapeutic avenue, not just for AD, but also for CAA. We additionally provide complimentary results regarding this locus’ association with CAA and AD risk from analyses that we conducted parallel to Shade et al. 2024.
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APA 7th
Belloy, M. E., Graff-Radford, J., & Greicius, M. D. (2025). A Quantitative Trait Locus for Reduced MicroglialAPOEExpression Associates with Reduced Cerebral Amyloid Angiopathy. medRxiv. https://doi.org/10.1101/2025.03.10.25323519
Vancouver
Belloy ME, Graff-Radford J, Greicius MD. A Quantitative Trait Locus for Reduced MicroglialAPOEExpression Associates with Reduced Cerebral Amyloid Angiopathy. medRxiv. 2025. doi:10.1101/2025.03.10.25323519.
BibTeX
@article{belloy2025-266fe467,
author = {Belloy, M. E. and Graff-Radford, J. and Greicius, M. D.},
title = {{A Quantitative Trait Locus for Reduced MicroglialAPOEExpression Associates with Reduced Cerebral Amyloid Angiopathy}},
journal = {medRxiv},
year = {2025},
doi = {10.1101/2025.03.10.25323519},
url = {https://doi.org/10.1101/2025.03.10.25323519}
}
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Key findings
- They strongly affect Aβ burden in the brain parenchyma 1 , a core hallmark of AD, but also at the level of the brain vasculature, i.e. cerebral amyloid angiopathy (CAA) 1,3 , which in turn relates to increased risk for amyloid-related imaging abnormalities (ARIA) in APOE *4 carriers when receiving anti-Aβ antibody treatments 4 .
- Here, we extend on these findings, highlighting there is compelling evidence that their genetic signal for reduced CAA relates to an effect on reduced microglial APOE expression, which would importantly support the evidence in favor of “decreasing APOE levels” and further herald this promising therapeutic avenue, not just for AD, but also for CAA.
- We additionally provide complimentary results regarding this locus’ association with CAA and AD risk from analyses that we conducted parallel to Shade et al. 2024.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 19 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 12 of the 62 points we could judge it on, which is 19 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| 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 | 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) |
| 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 | 12 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 12 of the 62 points we could judge it on is 19 out of 100. |
| Total | 19 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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