Estrogen use, APOE, and cognitive decline: Evidence of gene–environment interaction
Abstract
OBJECTIVE: APOE-epsilon4 increases the risk of cognitive decline, while elderly women who take estrogen may have less risk of cognitive decline. The authors sought to determine whether estrogen use modifies the association between APOE-epsilon4 and cognitive decline. METHOD: - As part of the Cardiovascular Health Study, 3,393 Medicare-eligible women (> or =65 years) were randomly selected and recruited from Sacramento County, CA; Washington County, MD; Forsyth County, NC; and Pittsburgh, PA. Cognitive testing was administered annually; the authors studied the 2,716 women with cognitive testing on > or =2 visits. They analyzed change in score on the Modified Mini-Mental State Examination (3MS) as a function of estrogen use, APOE genotype, and baseline common and internal carotid artery wall thickening. RESULTS: A total of 297 (11%) women were current estrogen users and 336 (12%) were past estrogen users. Over the 6-year average follow-up, baseline current users declined 1.5 points on the 3MS whereas never users declined 2.7 points (p = 0.023). Compared with epsilon4-negative women, epsilon4-positive women had a greater adjusted hazard ratio of cognitive impairment (3MS < 80), hazard risk [HR] = 1.47; 95% CI, 1.13 to 1.90. There was an interaction between estrogen use and epsilon4 presence (p = 0.037). Among epsilon4-negative women, current estrogen use reduced the risk of adjusted cognitive impairment compared with never users by almost half (HR = 0.59; 95% CI, 0.36 to 0.99), whereas, it did not reduce the risk among epsilon4-positive women (current use, HR = 1.33; 95% CI, 0.74 to 2.42). Compared with never use, current estrogen use was associated with less internal and common carotid wall thickening in epsilon4-negative women but not in epsilon4-positive women (p for interaction < 0.05 for both). Differences remained after adjusting for age, education, race, and stroke. CONCLUSIONS: Estrogen use was associated with less cognitive decline among epsilon4-negative women but not epsilon4-positive women. Potential mechanisms, including carotid atherosclerosis, by which epsilon4 may interact with estrogen and cognition warrant further investigation.
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It is unclear whether the influence of APOE-e4 may depend on the sex hormone estrogen.
“It is unclear whether the influence of APOE‐e4 may depend on the sex hormone estrogen.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [315]
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- Authors
- Yaffe, K., Haan, M., Byers, A., Tangen, C., & Kuller, L.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Neurology
- Published
- 2000-05-23
- Volume
- 54
- Issue
- 10
- Pages
- 1949-1954
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W2004602458
- Cited by
- 371
- References
- 35
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 18 · 2023: 11 · 2022: 12 · 2021: 17 · 2020: 13 · 2019: 13 · 2018: 10 · 2017: 5 · 2016: 9 · 2015: 7 · 2014: 7 · 2013: 14 · 2012: 9
- FWCI
- 17.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01hc085083-027)
- National Institute on Aging (K23AG000888, K23-AG 00888)
- National Heart, Lung, and Blood Institute (N01HC-85083)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- estrogen use, APOE ε4, cognitive decline, cognitive impairment, postmenopausal women, carotid artery wall thickening, carotid atherosclerosis, gene-environment interaction, cardiovascular risk factors, older women
- MeSH terms
- Aged, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Humans, Mental Status Schedule, Neuropsychological Tests, Risk Factors, Estrogen Replacement Therapy, Carotid Stenosis, Apolipoprotein E4
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