title: Estrogen receptor-alpha variants increase risk of Alzheimer's disease in women with Down syndrome.
abstract: BACKGROUND
  Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). Two tightly linked polymorphisms (PvuII and XbaI) in the first intron of estrogen receptor 1 (ESR1), the gene for ER-alpha, have been reported to influence estrogen receptor expression and may influence the risk of AD.
  
  
  METHODS
  We examined the relation of polymorphisms in ESR1 to the risk of AD in women with Down syndrome. The subjects (181 women with DS, 41-78 years of age) were followed at 14- to 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record reviews and neurological examinations was used to classify dementia. Genomic DNA was genotyped for 5 single-nucleotide polymorphisms in the upstream region and the first exon/intron of the ESR1 gene. Their association with dementia risk was evaluated, adjusting for covariates.
  
  
  RESULTS
  Women with at least 1 copy of the C allele at rs2234693 (PvuII) and those homozygous for the C allele at rs2077647 had an almost 3-fold increase in the risk of AD, compared with women without the C allele. The increased risks were independent of the apolipoprotein E genotype.
  
  
  CONCLUSIONS
  These findings support a role for estrogen receptor activity in the development of AD in women with Down syndrome.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, G.H. Sergievsky Center, New York, NY, USA. ns24@columbia.edu
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupf
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Michelle
authors.initials: M
authors.lastname: Wei
authors.forename: Deborah
authors.initials: D
authors.lastname: Pang
authors.forename: Constance
authors.initials: C
authors.lastname: Chace
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.forename: Warren B
authors.initials: WB
authors.lastname: Zigman
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
authors.forename: Wayne
authors.initials: W
authors.lastname: Silverman
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D004314:Down Syndrome / Q000453:epidemiology* / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D053327:Apolipoprotein E4; D047628:Estrogen Receptor alpha