Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk
Andrés Peña‐Tauber, Ricardo Hernández Arriaza, Dylan Reil, Manon Muntaner, Junyoung Park, Benjamin Grenier‐Boley, Marc Hulsman, Philippe Amouyel et al.. Annals of Neurology, 2026-08-03
Topic: Amyloid, tau and blood-test diagnosis
Damaging nonsynonymous ABCA1 variants had differential AD risk effects between APOE genotype groups and exhibited interaction effects with APOE ε2 and ε4. Predicted ABCA1 activity based on HDL-associated variants was associated with reduced AD risk and interacted with APOE ε4. Replication analyses suggested similar differences in effect size of ABCA1 variants between APOE groups and had concordant effect directions, although not statistically significant, in the APOE interaction model. ABCA1 missense variants N1800H and E1172D were strongly associated with plasma HDL and interacted with APOE in AD risk. In cell-based assays, ABCA1-N1800H showed plasma membrane localization defects potentially driven by misfolding. Genetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026;100:737-750.
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APA 7th
Peña‐Tauber, A., Arriaza, R. H., Reil, D., Muntaner, M., Park, J., Grenier‐Boley, B., et al. (2026). Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk. Annals of Neurology. https://doi.org/10.1002/ana.78303
Vancouver
Peña‐Tauber A, Arriaza RH, Reil D, Muntaner M, Park J, Grenier‐Boley B, et al. Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk. Annals of Neurology. 2026. doi:10.1002/ana.78303. PMID: 42548036.
BibTeX
@article{penatauber2026-42548036,
author = {Peña‐Tauber, Andrés and Arriaza, Ricardo Hernández and Reil, Dylan and Muntaner, Manon and Park, Junyoung and Grenier‐Boley, Benjamin and Hulsman, Marc and Amouyel, Philippe and others},
title = {{Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk}},
journal = {Annals of Neurology},
year = {2026},
doi = {10.1002/ana.78303},
pmid = {42548036},
url = {https://doi.org/10.1002/ana.78303}
}
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Key findings
- Damaging nonsynonymous ABCA1 variants had differential AD risk effects between APOE genotype groups and exhibited interaction effects with APOE ε2 and ε4.
- Predicted ABCA1 activity based on HDL-associated variants was associated with reduced AD risk and interacted with APOE ε4.
- Replication analyses suggested similar differences in effect size of ABCA1 variants between APOE groups and had concordant effect directions, although not statistically significant, in the APOE interaction model.
- ABCA1 missense variants N1800H and E1172D were strongly associated with plasma HDL and interacted with APOE in AD risk.
- In cell-based assays, ABCA1-N1800H showed plasma membrane localization defects potentially driven by misfolding.
Why it matters
This study found that damaging nonsynonymous ABCA1 variants had differential Alzheimer disease risk effects between APOE genotype groups and interacted with APOE ε2 and ε4. Predicted ABCA1 activity based on HDL-associated variants was associated with reduced Alzheimer disease risk and interacted with APOE ε4, though replication analyses were not statistically significant in the APOE interaction model.
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Study details
- Evidence strengthModerate
How this study scored 43/100
Published in a leading specialty 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 | 9 / 10 | Tier 2 — leading specialty journal (Annals of Neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (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 | 3 / 5 | Rated “moderate” 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 | 3 / 4 | Last-listed author Michael D. Greicius: h-index 65 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Stanford University: institution h-index 2,684 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 32 institution(s) in 6 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 42548036) |
| Free to read | 2 / 2 | Free to read |
| Total | 43 / 100 | — |
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