Exploring potential mechanisms of an African protective locus for Alzheimer's disease in APOEε4 carriers
Luciana Bertholim Nasciben, Karen Nuytemans, Derek J. Van Booven, Farid Rajabli, Sofia Moura, Aura María Ramírez, Griffin S. Parker, Derek M. Dykxhoorn et al.. Alzheimer s & Dementia, 2025-07-01
Topic: Amyloid, tau and blood-test diagnosis
> 0.95) and is present in all African ancestry tested. We identified methylation differences between the non-protective and rs10423769_A haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2-family transcription factor binding motifs in LD with the protective haplotype. Further, rs10423769 is an eQTL for ZNF222. The protective haplotype is unique, with haplotype changes in DNA methylation and SV that could contribute to the protective mechanism of rs10423769_A. The study generates hypothesis for future studies on this important protective mechanism for APOEε4 carriers. HIGHLIGHTS: We investigated an African-specific haplotype harboring a protective locus for APOEε4 carriers that significantly reduces the risk for Alzheimer Disease. The protective locus lies in an area of segmental duplications 2MB from APOE. We found that the protective haplotype is unique within the segmental duplications. The haplotype is found in all African ancestry tested but not in other ancestries. Long read whole genome sequencing identified an expanded VNTR associated with the protective haplotype containing multiple MEF2 transcription factor binding motifs. Differences in DNA methylation were found between the protective and the reference haplotype.
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APA 7th
Nasciben, L. B., Nuytemans, K., Van Booven, D. J., Rajabli, F., Moura, S., Ramírez, A. M., et al. (2025). Exploring potential mechanisms of an African protective locus for Alzheimer's disease in APOEε4 carriers. Alzheimer s & Dementia. https://doi.org/10.1002/alz.70500
Vancouver
Nasciben LB, Nuytemans K, Van Booven DJ, Rajabli F, Moura S, Ramírez AM, et al. Exploring potential mechanisms of an African protective locus for Alzheimer's disease in APOEε4 carriers. Alzheimer s & Dementia. 2025. doi:10.1002/alz.70500. PMID: 40704449.
BibTeX
@article{nasciben2025-40704449,
author = {Nasciben, Luciana Bertholim and Nuytemans, Karen and Van Booven, Derek J. and Rajabli, Farid and Moura, Sofia and Ramírez, Aura María and Parker, Griffin S. and Dykxhoorn, Derek M. and others},
title = {{Exploring potential mechanisms of an African protective locus for Alzheimer's disease in APOEε4 carriers}},
journal = {Alzheimer s \& Dementia},
year = {2025},
doi = {10.1002/alz.70500},
pmid = {40704449},
url = {https://doi.org/10.1002/alz.70500}
}
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Key findings
- > 0.95) and is present in all African ancestry tested.
- We identified methylation differences between the non-protective and rs10423769_A haplotypes.
- An expanded variable number tandem repeat (VNTR) containing multiple MEF2-family transcription factor binding motifs in LD with the protective haplotype.
- Further, rs10423769 is an eQTL for ZNF222.
- The protective haplotype is unique, with haplotype changes in DNA methylation and SV that could contribute to the protective mechanism of rs10423769_A.
Why it matters
This study investigated an African-specific haplotype harboring a protective locus for APOE ε4 carriers that significantly reduces Alzheimer disease risk. It found the protective haplotype is unique within segmental duplications, is present in all African ancestry tested but not other ancestries, and is associated with differences in DNA methylation and an expanded VNTR.
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Study details
- Evidence strengthLow
How this study scored 40/100
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 (Alzheimer s & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (OpenAlex, 2026-10-29) |
| 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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 1 / 4 | Cited 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Jeffery M. Vance: h-index 94 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Emory University: institution h-index 1,360 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40704449) |
| Free to read | 2 / 2 | Free to read |
| Total | 40 / 100 | — |
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