Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study
Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC, Cache County Study Investigators.. Archives of general psychiatry, 2004-05-01
Topic: Amyloid, tau and blood-test diagnosis
Background The incidence of Alzheimer disease (AD) increases strongly with age, but little is known about the cumulative incidence of AD over a lifetime of 100 years, or its relationship to the polymorphic APOE locus that encodes apolipoprotein E. APOE is a strong genetic risk factor for AD. Objectives To estimate the occurrence of AD as a function of age and number of APOE epsilon4 alleles; and to explore evidence for heterogeneity of AD risk related to APOE genotype and to other sources. Design Nonparametric and parametric survival analyses of AD incidence in prospective longitudinal study. Setting and participants A total of 3308 elderly residents of Cache County, Utah. Main outcome measures Cumulative incidence of AD; in mixture models assuming susceptible and nonsusceptible individuals, the proportion of individuals not susceptible to AD at any age. Results Models that assumed a proportion of invulnerable individuals provided strongly improved fit to the data. These models estimated the 100-year lifetime incidence of AD at 72%, implying that 28% of individuals would not develop AD over any reasonable life expectancy. We confirmed the acceleration of AD onset in individuals with 1 or, especially, 2 APOE, epsilon4 alleles but observed no meaningful difference in 100-year lifetime incidence related to number of epsilon4 alleles. Conclusions The APOE epsilon4 allele acts as a potent risk factor for AD by accelerating onset. However, the risk of AD appears heterogeneous in ways independent of APOE. Some individuals seem destined to escape AD, even over an extended lifespan. Their relative invulnerability may reflect other genes or environmental factors that can be investigated.
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APA 7th
Khachaturian, A. S., Corcoran, C. D., Mayer, L. S., Zandi, P. P., Breitner, J. C., & Cache County Study Investigators. (2004). Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study. Archives of general psychiatry. https://doi.org/10.1001/archpsyc.61.5.518
Vancouver
Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC, Cache County Study Investigators. Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study. Archives of general psychiatry. 2004. doi:10.1001/archpsyc.61.5.518. PMID: 15123497.
BibTeX
@article{khachaturian2004-15123497,
author = {Khachaturian, A. S. and Corcoran, C. D. and Mayer, L. S. and Zandi, P. P. and Breitner, J. C. and {Cache County Study Investigators}},
title = {{Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study}},
journal = {Archives of general psychiatry},
year = {2004},
doi = {10.1001/archpsyc.61.5.518},
pmid = {15123497},
url = {https://doi.org/10.1001/archpsyc.61.5.518}
}
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Key findings
- Results Models that assumed a proportion of invulnerable individuals provided strongly improved fit to the data.
Why it matters
In 3308 elderly residents of Cache County, the APOE ε4 allele accelerated the age at onset of Alzheimer's disease but did not meaningfully change the estimated 100-year lifetime incidence, which was 72%. This describes how APOE ε4 affects timing rather than whether a person develops the disease, and it does not test any treatment, cure, or prevention.
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Study details
- Study designlongitudinal study
- Participants3,308
- Evidence strengthModerate
How this study scored 59/100
Published in a peer-reviewed journal, and it is a longitudinal study following the same people over time. Scored zero for effect reported and randomised / blinded because the record does not state it. We have no data on institution's track record, so that was left out: it earned 57 of the 97 points we could judge it on, which is 59 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Archives of general psychiatry) |
| Journal's citation record | 4 / 4 | Archives of General Psychiatry: journal h-index 543 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A longitudinal study following the same 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 | 1 / 5 | 2004 — older than 20 years, still counted |
| Sample size | 3 / 4 | 3,308 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 | 5 / 7 | Cited 175 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 7.3 citations a year over 24 year(s) since 2004 |
| Impact for its field and year | 4 / 6 | Cited 9.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 15 other studies in this library |
| Still being cited | 1 / 4 | Cited 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Ara S. Khachaturian: h-index 36 (OpenAlex, whole career) |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 0 institution(s) in 0 countries — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 15123497) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 57 / 97 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 57 of the 97 points we could judge it on is 59 out of 100. |
| Total | 59 / 100 | — |
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