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APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease
Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqué-Alcázar L, Videla L, Gispert JD et al.. Nature medicine, 2024-05-06
Topic: Amyloid, tau and blood-test diagnosis
This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer's disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer's Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.
Key findings
- Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes.
- The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.
Why it matters
This analysis found that almost all APOE4 homozygotes exhibited Alzheimer's disease pathology and had significantly higher levels of Alzheimer's biomarkers from age 55 compared to APOE3 homozygotes, with earlier symptom onset at 65.1 years. The study concludes that APOE4 homozygotes represent a genetic form of Alzheimer's disease, suggesting the need for individualized prevention strategies, clinical trials, and treatments.
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Study details
- Participants3,297
- Evidence strengthLow
How this study scored 69/100
Published in a top-tier journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature medicine) |
| Journal's citation record | 4 / 4 | Nature Medicine: journal h-index 763 (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 | 2024 — within 3 year(s) of the newest study here |
| Sample size | 3 / 4 | 3,297 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 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 362 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 90.5 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 6 / 6 | Cited 86.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 25 other studies in this library |
| Still being cited | 4 / 4 | Cited 361 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Víctor Montal: h-index 29 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 18 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38710950) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 69 / 100 | — |
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Read the original
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
Fortea, J., Pegueroles, J., Alcolea, D., Belbin, O., Dols-Icardo, O., Vaqué-Alcázar, L., et al. (2024). APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Nature medicine. https://doi.org/10.1038/s41591-024-02931-w
Vancouver
Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqué-Alcázar L, et al. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Nature medicine. 2024. doi:10.1038/s41591-024-02931-w. PMID: 38710950.
BibTeX
@article{fortea2024-38710950,
author = {Fortea, J. and Pegueroles, J. and Alcolea, D. and Belbin, O. and Dols-Icardo, O. and Vaqué-Alcázar, L. and Videla, L. and Gispert, J. D. and others},
title = {{APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease}},
journal = {Nature medicine},
year = {2024},
doi = {10.1038/s41591-024-02931-w},
pmid = {38710950},
url = {https://doi.org/10.1038/s41591-024-02931-w}
}
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