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

Background: Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease ( AD). Two tightly linked polymorphisms ( Pvu II 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 ( Pvu II) 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. Copyright (c) 2008 S. Karger AG, Basel.