Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer’s Disease
Nicholas R. Ray, Joseph L. Bradley, Elanur Yılmaz, Çağhan Kızıl, Jiji Thulaseedhara Kurup, Eden R. Martin, Hans‐Ulrich Klein, Brian W. Kunkle et al.. PLoS Genetics, 2025-03-17
Topic: Amyloid, tau and blood-test diagnosis
The genetic component of early-onset Alzheimer disease (EOAD), accounting for ~10% of all Alzheimer's disease (AD) cases, is largely unexplained. Recent studies suggest that EOAD may be enriched for variants acting in the lipid pathway. The current study examines the shared genetic heritability between EOAD and the lipid pathway using genome-wide multi-trait genetic covariance analyses. Summary statistics were obtained from the GWAS meta-analyses of EOAD by the Alzheimer's Disease Genetics Consortium (n=19,668) and five blood lipid traits by the Global Lipids Genetics Consortium (n=1,320,016). The significant results were compared between the EOAD and lipids GWAS and genetic covariance analyses were performed via SUPERGNOVA. Genes in linkage disequilibrium (LD) with top EOAD hits in identified regions of covariance with lipid traits were scored and ranked for causality by combining evidence from gene-based analysis, AD-risk scores incorporating transcriptomic and proteomic evidence, eQTL data, eQTL colocalization analyses, DNA methylation data, and single-cell RNA sequencing analyses. Direct comparison of GWAS results showed 5 loci overlapping between EOAD and at least one lipid trait harboring APOE, TREM2, MS4A4E, LILRA5, and LRRC25. Local genetic covariance analyses identified 3 regions of covariance between EOAD and at least one lipid trait. Gene prioritization nominated 3 likely causative genes at these loci: ANKDD1B, CUZD1, and MS4A64.The current study identified genetic covariance between EOAD and lipids, providing further evidence of shared genetic architecture and mechanistic pathways between the two traits.
Key findings
- Recent studies suggest that EOAD may be enriched for variants acting in the lipid pathway.
- The significant results were compared between the EOAD and lipids GWAS and genetic covariance analyses were performed via SUPERGNOVA.
- Direct comparison of GWAS results showed 5 loci overlapping between EOAD and at least one lipid trait harboring APOE, TREM2, MS4A4E, LILRA5, and LRRC25.
Why it matters
This genetic analysis found shared genetic factors between early-onset Alzheimer disease and blood lipid traits, identifying overlapping loci including APOE and TREM2. It suggests that lipid pathways may be involved in early-onset Alzheimer disease, but no treatment or prevention is tested.
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Study details
- Study designmeta-analysis
- Participants19,668
- Evidence strengthHigh
How this study scored 65/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies. Scored zero for effect reported because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (PLoS Genetics) |
| Journal's citation record | 3 / 4 | PLoS Genetics: journal h-index 341 (OpenAlex, 2026-10-29) |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” 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 | 4 / 4 | 19,668 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 | A review of other studies — randomisation is not credited here |
| Times cited | 2 / 7 | Cited 5 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.7× 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 | 1 / 4 | Cited 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Christiane Reitz: h-index 50 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40096060) |
| Free to read | 2 / 2 | Free to read |
| Total | 65 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1371/journal.pgen.1011631
- PubMed: 40096060
- Original source →
- Free full text: PLoS Genetics →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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
Ray, N. R., Bradley, J. L., Yılmaz, E., Kızıl, Ç., Kurup, J. T., Martin, E. R., et al. (2025). Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer’s Disease. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1011631
Vancouver
Ray NR, Bradley JL, Yılmaz E, Kızıl Ç, Kurup JT, Martin ER, et al. Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer’s Disease. PLoS Genetics. 2025. doi:10.1371/journal.pgen.1011631. PMID: 40096060.
BibTeX
@article{ray2025-40096060,
author = {Ray, Nicholas R. and Bradley, Joseph L. and Yılmaz, Elanur and Kızıl, Çağhan and Kurup, Jiji Thulaseedhara and Martin, Eden R. and Klein, Hans‐Ulrich and Kunkle, Brian W. and others},
title = {{Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer’s Disease}},
journal = {PLoS Genetics},
year = {2025},
doi = {10.1371/journal.pgen.1011631},
pmid = {40096060},
url = {https://doi.org/10.1371/journal.pgen.1011631}
}
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