Peruvian Population Empowers Discovery of a TREM2 Missense Variant in Alzheimer Disease
Bilçağ Akgün, Mario R Cornejo-Olivas, Pedro Ramon Mena, Larry Deon Adams, Katrina Celis, Patrice G. Whitehead, Kara L. Hamilton‐Nelson, Julia Ríos‐Pinto et al.. Alzheimer s & Dementia, 2025-12-01
Topic: Brain proteins, microglia and lab models
Abstract Background Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD) and maximizing the opportunities for identifying genetic protective and risk alleles. The Peruvian population, with up to ∼80% of Amerindian ancestry, provides a unique opportunity to leverage Amerindian ancestry for deeper insights into AD mechanism. We performed the genome‐wide association study (GWAS) in the Peruvian population to characterize known AD genetic risk loci. Method 567 individuals (215 AD; 352 cognitively unimpaired) were included in these analyses. We performed GWAS on the Whole Genome Sequencing (WGS) dataset using a generalized linear mixed model, adjusting for sex, age, and population substructure as fixed effects and the genetic relationship matrix as a random effect. For follow‐up analysis, we extracted all nominal significant known AD variants and calculated linkage disequilibrium (LD) with surrounding SNPs. Variants with an R 2 ≥ 0.8 with the index SNP were annotated and further evaluated. To assess whether the associations were ancestry‐specific, we calculated the local ancestry of the regions corresponding to these variants. Result We replicated two known AD loci APOE4 allele and TREML2 marker (rs60755019). Fine‐mapping analysis at the TREML2 loci identified a TREM2 missense exonic marker (p.H157Y, OR=3.3 [1.9‐5.9], p = 4x10 ‐5 , CADD=23.2) having strong LD with the TREML2 risk marker in Peruvians. LA analysis showed that p.H157Y is located on an Amerindian ancestral background. p.H157Y is extremely rare across frequency databases (gnomAD, HGDP, and 1000 Genomes) except in Admixed American population ∼0.02. Additionally, APOE showed a strong association with AD, with an effect size (OR=4.3 [3.0‐6.1], p = 4x10 ‐15 ) higher that was observed in non‐Hispanic White populations. Conclusion Peruvian GWAS identified Amerindian ancestry specific exonic AD susceptibility variant p.H157Y. This variant has been previously reported as AD marker in Han Chinese populations with extreme effect size, but its rarity and contradictory findings in other groups suggest a potential ancestry‐specific effect. Functional studies indicate that it may enhance TREM2 shedding, impacting microglial function and contributing to AD pathogenesis. These observations highlight the power of examining diverse populations to gain a more comprehensive view of the genetic architecture of AD.
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APA 7th
Akgün, B., Cornejo-Olivas, M. R., Mena, P. R., Adams, L. D., Celis, K., Whitehead, P. G., et al. (2025). Peruvian Population Empowers Discovery of a TREM2 Missense Variant in Alzheimer Disease. Alzheimer s & Dementia. https://doi.org/10.1002/alz70855_105970
Vancouver
Akgün B, Cornejo-Olivas MR, Mena PR, Adams LD, Celis K, Whitehead PG, et al. Peruvian Population Empowers Discovery of a TREM2 Missense Variant in Alzheimer Disease. Alzheimer s & Dementia. 2025. doi:10.1002/alz70855_105970. PMID: 41444117.
BibTeX
@article{akgun2025-41444117,
author = {Akgün, Bilçağ and Cornejo-Olivas, Mario R and Mena, Pedro Ramon and Adams, Larry Deon and Celis, Katrina and Whitehead, Patrice G. and Hamilton‐Nelson, Kara L. and Ríos‐Pinto, Julia and others},
title = {{Peruvian Population Empowers Discovery of a TREM2 Missense Variant in Alzheimer Disease}},
journal = {Alzheimer s \& Dementia},
year = {2025},
doi = {10.1002/alz70855_105970},
pmid = {41444117},
url = {https://doi.org/10.1002/alz70855_105970}
}
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Key findings
- For follow‐up analysis, we extracted all nominal significant known AD variants and calculated linkage disequilibrium (LD) with surrounding SNPs.
- Result We replicated two known AD loci APOE4 allele and TREML2 marker (rs60755019).
- LA analysis showed that p.H157Y is located on an Amerindian ancestral background. p.H157Y is extremely rare across frequency databases (gnomAD, HGDP, and 1000 Genomes) except in Admixed American population ∼0.02.
- Functional studies indicate that it may enhance TREM2 shedding, impacting microglial function and contributing to AD pathogenesis.
Why it matters
This genome-wide association study in the Peruvian population replicated the known APOE4 and TREML2 Alzheimer disease loci and identified a rare TREM2 missense variant, p.H157Y, on an Amerindian ancestral background. Functional studies suggest the variant may enhance TREM2 signaling, but the work is genetic and does not itself test a treatment.
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Study details
- Participants567
- Effect sizeOR=3.3; OR=4.3
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design 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 | 2 / 4 | 567 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| 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 | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 0 / 6 | Cited 0.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 0 / 4 | Last-listed author Alzheimer's Disease Sequencing Project: h-index 2 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Miami: institution h-index 998 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41444117) |
| Free to read | 2 / 2 | Free to read |
| Total | 39 / 100 | — |
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Read the original
- DOI: 10.1002/alz70855_105970
- PubMed: 41444117
- Original source →
- Free full text: Alzheimer s & Dementia →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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