Apolipoprotein E: risk factor for Alzheimer disease
Tsai MS, Tangalos EG, Petersen RC, Smith GE, Schaid DJ, Kokmen E, Ivnik RJ, Thibodeau SN.. American journal of human genetics, 1994-04-01
Topic: Amyloid, tau and blood-test diagnosis
The apolipoprotein E gene (APOE) has three common alleles (epsilon 2, epsilon 3, and epsilon 4) that determine six genotypes in the general population. In this study, we examined 77 patients with late-onset Alzheimer disease (AD), along with an equal number of age- and sex-matched controls, for an association with the APOE-epsilon 4 allele. We show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with the APOE-epsilon 4/epsilon 3 genotype being the most common in the AD group and the APOE-epsilon 3/epsilon 3 being the most common in the control group. In the AD group, homozygosity for epsilon 4 was found in nine individuals, whereas none was found in the control group. The odds ratio for AD, when associated with one or two epsilon 4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-epsilon 4, was 3.6 (95% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from 83 to 78 to 74 years as the number of APOE-epsilon 4 alleles increased from 0 to 1 to 2, respectively (test for trend, P = .001). Our data, which are in agreement with recent reports, suggest that the APOE-epsilon 4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population.
Key findings
- We show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006).
- The odds ratio for AD, when associated with one or two epsilon 4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-epsilon 4, was 3.6 (95% CI 1.5-9.8).
- Our data, which are in agreement with recent reports, suggest that the APOE-epsilon 4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population.
Why it matters
In this case-control study, the APOE epsilon4 allele was significantly more frequent in late-onset Alzheimer disease patients than controls, and the median age at onset decreased as the number of epsilon4 alleles increased. This supports APOE epsilon4 as a risk factor for Alzheimer disease but does not offer a treatment or cure.
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Study details
- Participants77
- Evidence strengthLow
How this study scored 45/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, so that was left out: it earned 43 of the 96 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (American journal of human genetics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 1 / 5 | 1994 — older than 20 years, still counted |
| Sample size | 1 / 4 | 77 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 258 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 7.6 citations a year over 34 year(s) since 1994 |
| Impact for its field and year | 4 / 6 | Cited 17.3× 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 | 1 / 4 | Cited 9 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Stephen N. Thibodeau: h-index 120 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 8128961) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 43 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 43 of the 96 points we could judge it on is 45 out of 100. |
| Total | 45 / 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. This record has no DOI, so the citation leaves it out. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Tsai, M. S., Tangalos, E. G., Petersen, R. C., Smith, G. E., Schaid, D. J., Kokmen, E., et al. (1994). Apolipoprotein E: risk factor for Alzheimer disease. American journal of human genetics.
Vancouver
Tsai MS, Tangalos EG, Petersen RC, Smith GE, Schaid DJ, Kokmen E, et al. Apolipoprotein E: risk factor for Alzheimer disease. American journal of human genetics. 1994. PMID: 8128961.
BibTeX
@article{tsai1994-8128961,
author = {Tsai, M. S. and Tangalos, E. G. and Petersen, R. C. and Smith, G. E. and Schaid, D. J. and Kokmen, E. and Ivnik, R. J. and Thibodeau, S. N.},
title = {{Apolipoprotein E: risk factor for Alzheimer disease}},
journal = {American journal of human genetics},
year = {1994},
pmid = {8128961}
}
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