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Multimodal mediators connecting APOE4 to dementia
Chen Z, Lin F, Yang K, Tang W, Li J, Niu J, Shi Y, Zhou S et al.. Research Square, 2026-10-21
Topic: Genetics and APOE
We revealed graded, allele dosage‑dependent risk elevations for ACD, AD and VaD among APOE4 carriers, whereby homozygous carriers exhibited substantially higher incident dementia risk relative to heterozygous carriers and non‑carriers across all three clinical endpoints. Bilateral hippocampal and left thalamic gray matter atrophy selectively mediated APOE4 -associated ACD and AD risk without detectable indirect effects on VaD, while widespread white matter microstructural degeneration mediated increased risk across all three dementia subtypes. At the peripheral molecular level, circulating GFAP served as a shared protein mediator for ACD, AD and VaD, whereas distinct proteomic and metabolomic profiles underpinned subtype-specific pathways for AD and VaD, respectively. Combined models integrating plasmamediators outperformed clinical-only models for predicting incident dementia in both APOE4 heterozygotes and homozygotes. Collectively, this study delineates coordinated central brain structural and circulating molecular mediators of APOE4 -associated dementia risk, and provides potential subtype-specific mechanistic insights and therapeutic targets for AD and VaD.
Key findings
- We revealed graded, allele dosage‑dependent risk elevations for ACD, AD and VaD among APOE4 carriers, whereby homozygous carriers exhibited substantially higher incident dementia risk relative to heterozygous carriers and non‑carriers across all three clinical endpoints.
- Bilateral hippocampal and left thalamic gray matter atrophy selectively mediated APOE4 -associated ACD and AD risk without detectable indirect effects on VaD, while widespread white matter microstructural degeneration mediated increased risk across all three dementia subtypes.
- At the peripheral molecular level, circulating GFAP served as a shared protein mediator for ACD, AD and VaD, whereas distinct proteomic and metabolomic profiles underpinned subtype-specific pathways for AD and VaD, respectively.
- Combined models integrating plasmamediators outperformed clinical-only models for predicting incident dementia in both APOE4 heterozygotes and homozygotes.
- Collectively, this study delineates coordinated central brain structural and circulating molecular mediators of APOE4 -associated dementia risk, and provides potential subtype-specific mechanistic insights and therapeutic targets for AD and VaD.
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Study details
- Participants58,876
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 32 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported 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 20 of the 62 points we could judge it on, which is 32 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| 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 | 4 / 4 | 58,876 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| 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 | 20 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 20 of the 62 points we could judge it on is 32 out of 100. |
| Total | 32 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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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
Chen, Z., Lin, F., Yang, K., Tang, W., Li, J., Niu, J., et al. (2026). Multimodal mediators connecting APOE4 to dementia. Research Square. https://doi.org/10.21203/rs.3.rs-11445203/v1
Vancouver
Chen Z, Lin F, Yang K, Tang W, Li J, Niu J, et al. Multimodal mediators connecting APOE4 to dementia. Research Square. 2026. doi:10.21203/rs.3.rs-11445203/v1.
BibTeX
@article{chen2026-e0e0d44c,
author = {Chen, Z. and Lin, F. and Yang, K. and Tang, W. and Li, J. and Niu, J. and Shi, Y. and Zhou, S. and others},
title = {{Multimodal mediators connecting APOE4 to dementia}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11445203/v1},
url = {https://doi.org/10.21203/rs.3.rs-11445203/v1}
}
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