APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease
Thomassen JQ, Leonard H, Ulms B, Grenier-Boley B, Heikkinen S, Garcia-González P, Castillo-Morales A, Kikuchi M, Gim J, Cao H, Küçükali F, Amin N, et al.. Nature genetics, 2026-09-14
Topic: Amyloid, tau and blood-test diagnosis
Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies 1-10 . Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers 11-13 , hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.
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APA 7th
Thomassen, J. Q., Leonard, H., Ulms, B., Grenier-Boley, B., Heikkinen, S., Garcia-González, P., et al. (2026). APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease. Nature genetics. https://doi.org/10.1038/s41588-026-02713-9
Vancouver
Thomassen JQ, Leonard H, Ulms B, Grenier-Boley B, Heikkinen S, Garcia-González P, et al. APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease. Nature genetics. 2026. doi:10.1038/s41588-026-02713-9. PMID: 42736378.
BibTeX
@article{thomassen2026-42736378,
author = {Thomassen, J. Q. and Leonard, H. and Ulms, B. and Grenier-Boley, B. and Heikkinen, S. and Garcia-González, P. and Castillo-Morales, A. and Kikuchi, M. and Gim, J. and Cao, H. and Küçükali, F. and Amin, N. and others},
title = {{APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease}},
journal = {Nature genetics},
year = {2026},
doi = {10.1038/s41588-026-02713-9},
pmid = {42736378},
url = {https://doi.org/10.1038/s41588-026-02713-9}
}
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Key findings
- Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers 11-13 , hampering the treatment of those with the highest unmet need.
- To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status.
- HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status.
- DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases.
- Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.
Why it matters
By analyzing genes separately in APOE ε4 and ε2 carriers, the study found new genetic signals for Alzheimer's risk, including DDHD1. This is genetic risk research that may inform future targeted therapies, not a treatment or cure.
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Study details
- Study designcase-control
- Evidence strengthHigh
How this study scored 50/100
Published in a leading specialty journal, and it is a case-control study. Scored zero for sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 49 of the 98 points we could judge it on, which is 50 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature genetics) |
| Journal's citation record | 4 / 4 | Nature Genetics: journal h-index 776 (OpenAlex, 2026-10-29) |
| Study design | 6 / 12 | A case-control study |
| 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 | 5 / 5 | 2026 — within 1 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 | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| 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 | 2 / 4 | Last-listed author Eystein Stordal: h-index 40 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | National Institutes of Health: institution h-index 2,723 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 142 institution(s) in 23 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 42736378) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 49 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 49 of the 98 points we could judge it on is 50 out of 100. |
| Total | 50 / 100 | — |
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