Estrogen receptor-alpha 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 (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.
Schupf
Nicole
N
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
Lee
Joseph H
JH
Wei
Michelle
M
Pang
Deborah
D
Chace
Constance
C
Cheng
Rong
R
Zigman
Warren B
WB
Tycko
Benjamin
B
Silverman
Wayne
W
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
D053327:Apolipoprotein E4; D047628:Estrogen Receptor alpha