APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease
Quiroz YT, Aguillon D, Aguirre-Acevedo DC, Vasquez D, Zuluaga Y, Baena AY, Madrigal L, Hincapié L, Sanchez JS, Langella S, Posada-Duque R, Littau JL, et al.. New England Journal of Medicine, 2024-06-20
Topic: Amyloid, tau and blood-test diagnosis
Background Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant ( APOE3 Ch ). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. Methods We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. Results Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18 F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18 F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. Conclusions Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).
Key findings
- Methods We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant.
- Results Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49).
- In one of these participants, who underwent 18 F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred.
Why it matters
Among carriers of a PSEN1 mutation causing inherited Alzheimer disease, having one copy of the APOE3 Christchurch variant was linked to a later median age at cognitive impairment onset, 52 versus 47 years. This is a study of a rare inherited form of the disease in one Colombian kindred, so it points to a possible protective mechanism rather than a treatment.
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Study details
- Study designcohort
- Participants1,077
- Effect sizeMedian onset of cognitive impairment delayed from 47 to 52 years in APOE3 Christchurch heterozygotes
- Evidence strengthModerate
Limitations
Small number of people carrying both variants and a genetically homogeneous isolate population, which increases uncertainty in the age-at-onset estimates; the protective effect may not translate to sporadic Alzheimer's disease or other populations.
How this study scored 72/100
Published in a top-tier journal, and it is a cohort study following people over time. Scored zero for randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 71 of the 98 points we could judge it on, which is 72 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (New England Journal of Medicine) |
| Journal's citation record | 4 / 4 | New England Journal of Medicine: journal h-index 1,505 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A cohort study following people over time |
| 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 | 4 / 5 | 2024 — within 3 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,077 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 | 4 / 7 | Cited 62 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 15.5 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 4 / 6 | Cited 14.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 4 other studies in this library |
| Still being cited | 3 / 4 | Cited 62 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Joseph F. Arboleda‐Velásquez: h-index 29 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38899694) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 71 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 71 of the 98 points we could judge it on is 72 out of 100. |
| Total | 72 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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
Quiroz, Y. T., Aguillon, D., Aguirre-Acevedo, D. C., Vasquez, D., Zuluaga, Y., Baena, A. Y., et al. (2024). APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2308583
Vancouver
Quiroz YT, Aguillon D, Aguirre-Acevedo DC, Vasquez D, Zuluaga Y, Baena AY, et al. APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease. New England Journal of Medicine. 2024. doi:10.1056/NEJMoa2308583. PMID: 38899694.
BibTeX
@article{quiroz2024-38899694,
author = {Quiroz, Y. T. and Aguillon, D. and Aguirre-Acevedo, D. C. and Vasquez, D. and Zuluaga, Y. and Baena, A. Y. and Madrigal, L. and Hincapié, L. and Sanchez, J. S. and Langella, S. and Posada-Duque, R. and Littau, J. L. and others},
title = {{APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease}},
journal = {New England Journal of Medicine},
year = {2024},
doi = {10.1056/NEJMoa2308583},
pmid = {38899694},
url = {https://doi.org/10.1056/NEJMoa2308583}
}
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