Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease
Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A et al.. Annals of internal medicine, 2002-08-01
Topic: Amyloid, tau and blood-test diagnosis
Background Presence of the apolipoprotein E (apoE) epsilon4 allele, which is involved in cholesterol metabolism, is the most important genetic risk factor for Alzheimer disease. Elevated midlife values for total cholesterol level and blood pressure have been implicated recently as risk factors for Alzheimer disease. Objective To study the relative importance and the putative relationship among the apoE epsilon4 allele, midlife total cholesterol level, and midlife blood pressure as risk factors for late-life Alzheimer disease. Design Prospective population-based study. Setting Kuopio and Joensuu, eastern Finland. Participants Participants were derived from random population surveys from 1972, 1977, 1982, and 1987. A total of 1449 persons (73%), 65 to 79 years of age, participated in the reexamination in 1998 (mean follow-up, 21 years). Measurements Midlife blood pressure and total cholesterol level, apoE genotype, and development of Alzheimer disease during follow-up. Results The apoE epsilon4 allele was an independent risk factor for Alzheimer disease, even after adjustment for midlife vascular risk factors and other confounders (odds ratio, 2.1 [95% CI, 1.1 to 4.1]). Similarly, elevated midlife values for serum total cholesterol level (odds ratio, 2.8 [CI, 1.2 to 6.7]) and systolic blood pressure (odds ratio, 2.6 [CI, 1.1 to 6.6]) were independent risk factors for Alzheimer disease, even after adjustment for apoE genotype and other confounding factors. Conclusions The association between the apoE epsilon4 allele and Alzheimer disease does not seem to be mediated by vascular factors. The apoE epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for Alzheimer disease. The risk for Alzheimer disease from treatable factors--elevated total cholesterol level and blood pressure--appears to be greater than that from the apoE epsilon4 allele.
Key findings
- Results The apoE epsilon4 allele was an independent risk factor for Alzheimer disease, even after adjustment for midlife vascular risk factors and other confounders (odds ratio, 2.1 [95% CI, 1.1 to 4.1]).
Why it matters
In 1,449 people from eastern Finland followed for an average of 21 years, carrying the APOE ε4 gene variant (odds ratio 2.1), having raised total cholesterol in midlife (2.8) and having high systolic blood pressure in midlife (2.6) were each linked to Alzheimer's in later life, even after accounting for one another. The authors concluded that the risk from these "treatable factors" appears greater than the risk from ε4, but the three estimates have wide, overlapping confidence intervals. This was an observational study, so it does not show that lowering cholesterol or blood pressure prevents Alzheimer's.
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Study details
- Participants1,449
- Evidence strengthLow
How this study scored 58/100
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 (Annals of internal medicine) |
| Journal's citation record | 4 / 4 | Annals of Internal Medicine: journal h-index 648 (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 | 1 / 5 | 2002 — older than 20 years, still counted |
| Sample size | 3 / 4 | 1,449 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 646 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 24.8 citations a year over 26 year(s) since 2002 |
| Impact for its field and year | 4 / 6 | Cited 13.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 47 other studies in this library |
| Still being cited | 2 / 4 | Cited 49 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Hilkka S. Soininen: h-index 143 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Kuopio University Hospital: institution h-index 529 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 12160362) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 58 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Kivipelto, M., Helkala, E. L., Laakso, M. P., Hänninen, T., Hallikainen, M., Alhainen, K., et al. (2002). Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Annals of internal medicine. https://doi.org/10.7326/0003-4819-137-3-200208060-00006
Vancouver
Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Annals of internal medicine. 2002. doi:10.7326/0003-4819-137-3-200208060-00006. PMID: 12160362.
BibTeX
@article{kivipelto2002-12160362,
author = {Kivipelto, M. and Helkala, E. L. and Laakso, M. P. and Hänninen, T. and Hallikainen, M. and Alhainen, K. and Iivonen, S. and Mannermaa, A. and others},
title = {{Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease}},
journal = {Annals of internal medicine},
year = {2002},
doi = {10.7326/0003-4819-137-3-200208060-00006},
pmid = {12160362},
url = {https://doi.org/10.7326/0003-4819-137-3-200208060-00006}
}
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