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Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study
Myers RH, Schaefer EJ, Wilson PW, D'Agostino R, Ordovas JM, Espino A, Au R, White RF et al.. Neurology, 1996-03-01
Topic: Amyloid, tau and blood-test diagnosis
Apolipoprotein E type 4 allele (apoE epsilon4) is associated with Alzheimer's disease (AD) in the late-onset familial form and in sporadic cases, but the age-associated risk in a randomly sampled elderly population is not established. We examined the association of apoE epsilon4 with AD and other dementias (mainly multi-infarct or dementia following stroke) in 1,030 persons aged 71 to 100 years in the population-based Framingham Study cohort. Kaplan-Meier survival analysis revealed that 55% of the apoE epsilon4/epsilon4 homozygotes developed AD by age 80, whereas 27% of apoE epsilon3/epsilon4 heterozygotes developed AD by age 85, and 9% of those without a 4 allele developed AD by age 85 years. In comparison with persons without a 4 allele, the risk ration for AD was 3.7 (95% CI = 1.9 to 7.5) for apoE epsilon3/epsilon4 heterozygotes and 30.1 (95% CI = 10.7 to 84.4) for apoE epsilon4 homozygotes. ApoE epsilon2 (2/2, 2/3, or 2/4 genotypes) was associated with an absence of AD. One-half (n=21) of the 43 AD patients were either homozygous or heterozygous for apoE epsilon4. We found evidence for an association of apoE epsilon4 with other dementia, primarily multi-infarct dementia and stroke. The risk ratio was 2.3 (95% CI = 0.9 to 6.1) for non-AD dementias among persons with apoE epsilon3/epsilon4. Although the apoE epsilon4 allele is a potent risk factor for AD and may be associated with other forms of dementia, most apoE epsilon4 carriers do not develop dementia, and about one-half of AD is not apoE epsilon4 associated. The low positive predictive value of this marker (0.10) suggest that use of apoE genotyping as a screening test for AD is not supported.
Key findings
- Apolipoprotein E type 4 allele (apoE epsilon4) is associated with Alzheimer's disease (AD) in the late-onset familial form and in sporadic cases, but the age-associated risk in a randomly sampled elderly population is not established.
- Kaplan-Meier survival analysis revealed that 55% of the apoE epsilon4/epsilon4 homozygotes developed AD by age 80, whereas 27% of apoE epsilon3/epsilon4 heterozygotes developed AD by age 85, and 9% of those without a 4 allele developed AD by age 85 years.
- ApoE epsilon2 (2/2, 2/3, or 2/4 genotypes) was associated with an absence of AD.
- We found evidence for an association of apoE epsilon4 with other dementia, primarily multi-infarct dementia and stroke.
- Although the apoE epsilon4 allele is a potent risk factor for AD and may be associated with other forms of dementia, most apoE epsilon4 carriers do not develop dementia, and about one-half of AD is not apoE epsilon4 associated.
Why it matters
In this population-based cohort, people carrying the apolipoprotein E epsilon4 allele had a higher risk of developing Alzheimer's disease, with the highest risk in epsilon4 homozygotes. The study identifies a genetic risk factor only and reports no treatment, cure or prevention.
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Study details
- Participants21
- Evidence strengthModerate
How this study scored 53/100
Published in a leading specialty journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Neurology) |
| Journal's citation record | 4 / 4 | Neurology: journal h-index 525 (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 | 1 / 5 | 1996 — older than 20 years, still counted |
| Sample size | 1 / 4 | 21 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 346 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 10.8 citations a year over 32 year(s) since 1996 |
| Impact for its field and year | 4 / 6 | Cited 16.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 31 other studies in this library |
| Still being cited | 1 / 4 | Cited 9 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Phillip A. Wolf: h-index 16 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Boston University: institution h-index 1,456 (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 8618665) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
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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
Myers, R. H., Schaefer, E. J., Wilson, P. W., D'Agostino, R., Ordovas, J. M., Espino, A., et al. (1996). Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study. Neurology. https://doi.org/10.1212/wnl.46.3.673
Vancouver
Myers RH, Schaefer EJ, Wilson PW, D'Agostino R, Ordovas JM, Espino A, et al. Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study. Neurology. 1996. doi:10.1212/wnl.46.3.673. PMID: 8618665.
BibTeX
@article{myers1996-8618665,
author = {Myers, R. H. and Schaefer, E. J. and Wilson, P. W. and D'Agostino, R. and Ordovas, J. M. and Espino, A. and Au, R. and White, R. F. and others},
title = {{Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study}},
journal = {Neurology},
year = {1996},
doi = {10.1212/wnl.46.3.673},
pmid = {8618665},
url = {https://doi.org/10.1212/wnl.46.3.673}
}
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