title: Estrogen receptor polymorphisms and incident dementia: the prospective 3C study.
abstract: 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 α (ESR1) and β (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) ε4 allele, and hormone treatment were considered as potential effect modifiers of this association.
  
  
  RESULTS
  Among women, the CC genotype of ESR1rs2234693 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 ε4 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 ESR1rs2234693 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 ε4 allele.
authors.affiliation: Inserm, U1061, Neuropsychiatry: Epidemiological and Clinical Research, Montpellier, France; Université Montpellier1, Montpellier, France; Murdoch Children's Research Institute, Royal Children's Hospital, Victoria, Australia. Electronic address: joanne.ryan@inserm.fr.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ryan
authors.affiliation: Inserm, U1061, Neuropsychiatry: Epidemiological and Clinical Research, Montpellier, France; Université Montpellier1, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Carrière
authors.affiliation: Inserm, U1018, Université Paris Sud 11, Villejuif, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Carcaillon
authors.affiliation: Inserm, U897, Université Bordeaux 2, Bordeaux, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Dartigues
authors.affiliation: Inserm, U897, Université Bordeaux 2, Bordeaux, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Auriacombe
authors.affiliation: CHRU Dijon, Centre Mémoire Ressources et Recherche, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rouaud
authors.affiliation: Inserm, U1061, Neuropsychiatry: Epidemiological and Clinical Research, Montpellier, France; Université Montpellier1, Montpellier, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Berr
authors.affiliation: Inserm, U1061, Neuropsychiatry: Epidemiological and Clinical Research, Montpellier, France; Université Montpellier1, Montpellier, France; Faculty of Medicine, Imperial College, London, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Ritchie
authors.affiliation: Inserm, U1018, Université Paris Sud 11, Villejuif, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Scarabin
authors.affiliation: Inserm, U1061, Neuropsychiatry: Epidemiological and Clinical Research, Montpellier, France; Université Montpellier1, Montpellier, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Ancelin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000235:genetics; D015331:Cohort Studies; D003704:Dementia / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta
keywords: APOE; Alzheimer's disease; Cohort study; Dementia; ESR1; ESR2; Epidemiology; Estrogen receptor polymorphisms; Gender-specific