Journal
ALZHEIMERS & DEMENTIA
Volume 10, Issue 1, Pages 27-35Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2012.12.008
Keywords
Alzheimer's disease; Dementia; Estrogen receptor polymorphisms; ESR1; ESR2; Gender-specific; APOE; Epidemiology; Cohort study
Categories
Funding
- National Health and Medical Research Council [APP1012735]
- Fondation pour la Recherche Medicale
- Caisse Nationale Maladie des Travailleurs Salaries
- Direction Generale de la Sante
- MGEN
- Institut de la Longevite
- Agence Francaise de Securite Sanitaire des Produits de Sante
- Regional Government of Aquitaine
- Regional Government of Bourgogne
- Regional Government of Languedoc-Roussillon
- Fondation de France
- Ministry of Research-Inserm Programme Cohorts and collection of biological material
- Eisai
- Fondation Plan Alzheimer
- Agence Nationale de la Recherche [ANR 2007-LVIE-004, 2007-LVIE-005-01, 06-PNRA-005]
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Background: Genetic variation in the estrogen receptor (ESR) may be associated with the incidence of Alzheimer's disease (AD), but this association could be modified by genetic and environmental factors. Methods: The association between five ESR alpha (ESR1) and beta (ESR2) polymorphisms with 7-year dementia incidence was examined among 6959 older men and women from the Three City Study using multivariate-adjusted Cox regression models with delayed entry. Gender, the apolipoprotein E (APOE) epsilon 4 allele, and hormone treatment were considered as potential effect modifiers of this association. Results: Among women, the CC genotype of ESR1 rs2234693 was specifically associated with a small increased risk of AD (adjusted hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.03-2.28, P = .03). However, women with this genotype had a substantially increased risk of AD associated with the APOE epsilon 4 allele (adjusted HR: 3.24, 95% CI: 1.81-5.79 for women rs2234693 CC; compared with HR: 1.87, 95% CI: 1.37-2.56 for all women). There was also evidence of a nominally significant interaction between the ESR1 and ESR2 polymorphisms on the risk of all dementias (P = .04). Hormone treatment did not modify these associations, and there were no significant associations in men. Conclusions: Although there was only weak support for a gender-specific association between the common ESR1 rs2234693 polymorphism and AD, this polymorphism may act as an effect modifier, modifying the association between an ESR2 polymorphism and dementia, as well as the risk of AD associated with the APOE epsilon 4 allele. (C) 2014 The Alzheimer's Association. All rights reserved.
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