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The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons
Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L.. JAMA, 1999-07-01
Topic: Risk, prevention and care in population studies
Context Cognitive decline in elderly persons is often an early predictor of dementia. Subclinical cardiovascular disease (CVD) and diabetes mellitus may contribute to substantial decline in cognitive function in the elderly. These risks may be modified by gene-environment interactions between apolipoprotein E (APOE) genotype and CVD risk factors or subclinical CVD. Objectives To examine the association between subclinical CVD and decline in cognitive functioning in the elderly and to examine effect modification by the APOE genotype of the association between subclinical disease and cognitive decline. Design The Cardiovascular Health Study, a population-based, prospective cohort study. Setting and population A total of 5888 randomly selected Medicare-eligible participants from Sacramento County, California; Forsyth County, North Carolina; Washington County, Maryland; and Pittsburgh, Pa, aged 65 years or older, who were recruited in 1989-1990 (n = 5201) and in 1992-1993 (n = 687) and who were followed up for 7 and 5 years, respectively. Main outcome measures Change over time in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test as a function of APOE genotype, subclinical CVD, and diabetes mellitus. Results Seventy percent of participants had no significant decline on the Modified Mini-Mental State Examination. Systolic blood pressure, the ankle-arm brachial index, atherosclerosis of the internal carotid artery, diabetes mellitus, and several diagnoses of prevalent CVD were significantly associated with declines in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test. The rate of cognitive decline associated with peripheral vascular disease, atherosclerosis of the common and internal carotid arteries, or diabetes mellitus was increased by the presence of any APOE epsilon4 allele. Conclusions Most healthy elderly people did not experience cognitive decline. Measures of subclinical CVD were modest predictors of cognitive decline. Those with any APOE epsilon4 allele in combination with atherosclerosis, peripheral vascular disease, or diabetes mellitus were at substantially higher risk of cognitive decline than those without the APOE epsilon4 allele or subclinical CVD. High levels of atherosclerosis increased cognitive decline independently of APOE genotype.
Key findings
- Results Seventy percent of participants had no significant decline on the Modified Mini-Mental State Examination.
- Systolic blood pressure, the ankle-arm brachial index, atherosclerosis of the internal carotid artery, diabetes mellitus, and several diagnoses of prevalent CVD were significantly associated with declines in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test.
- The rate of cognitive decline associated with peripheral vascular disease, atherosclerosis of the common and internal carotid arteries, or diabetes mellitus was increased by the presence of any APOE epsilon4 allele.
- Those with any APOE epsilon4 allele in combination with atherosclerosis, peripheral vascular disease, or diabetes mellitus were at substantially higher risk of cognitive decline than those without the APOE epsilon4 allele or subclinical CVD.
Why it matters
In this cohort, several cardiovascular and diabetes measures were linked to declines in cognitive test scores. The study examined how APOE genotype might modify these links, but it does not show that treating these conditions prevents dementia.
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Study details
- Study designcohort study
- Participants5,201
- Evidence strengthModerate
How this study scored 65/100
Published in a top-tier journal, and it is a cohort study following people over time. Scored zero for effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (JAMA) |
| Journal's citation record | 4 / 4 | JAMA: journal h-index 1,011 (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 | 1 / 5 | 1999 — older than 20 years, still counted |
| Sample size | 3 / 4 | 5,201 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 459 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 15.8 citations a year over 29 year(s) since 1999 |
| Impact for its field and year | 4 / 6 | Cited 13.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 35 other studies in this library |
| Still being cited | 1 / 4 | Cited 11 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Mary N. Haan: h-index 74 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of California, Davis: institution h-index 1,257 (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 10404910) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 65 / 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. Check the citation against the original before you use it.
APA 7th
Haan, M. N., Shemanski, L., Jagust, W. J., Manolio, T. A., & Kuller, L. (1999). The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA. https://doi.org/10.1001/jama.282.1.40
Vancouver
Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA. 1999. doi:10.1001/jama.282.1.40. PMID: 10404910.
BibTeX
@article{haan1999-10404910,
author = {Haan, M. N. and Shemanski, L. and Jagust, W. J. and Manolio, T. A. and Kuller, L.},
title = {{The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons}},
journal = {JAMA},
year = {1999},
doi = {10.1001/jama.282.1.40},
pmid = {10404910},
url = {https://doi.org/10.1001/jama.282.1.40}
}
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