Estrogen receptor-α variants increase risk of Alzheimer's disease in women with down syndrome

Nicole Schupf, Joseph H. Lee, Michelle Wei, Deborah Pang, Constance Chace, Rong Cheng, Warren B. Zigman, Benjamin Tycko, Wayne Silverman

Research output: Contribution to journalArticlepeer-review


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-α, 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. Conclusion: These findings support a role for estrogen receptor activity in the development of AD in women with Down syndrome.

Original languageEnglish (US)
Pages (from-to)476-482
Number of pages7
JournalDementia and Geriatric Cognitive Disorders
Issue number5
StatePublished - Apr 2008
Externally publishedYes


  • Alzheimer's disease
  • Down syndrome
  • Estrogen
  • Estrogen receptor-α

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Cognitive Neuroscience
  • Psychiatry and Mental health


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