Estrogen receptor genotype and risk of cognitive impairment in elders: findings from the Health ABC study.
OBJECTIVE
To determine whether variants in the estrogen receptors 1 (alpha) and 2 (beta) (ESR1 and ESR2) genes are associated with cognitive impairment in non-demented elderly men and women.


BACKGROUND
Several single nucleotide polymorphisms (SNPs) on ESR1 and ESR2 genes have been associated with a range of hormone sensitive diseases such as breast cancer and osteoporosis. Genetic variations in ESR may also influence cognitive aging but are less studied, especially among men.


METHODS
We studied 2527 participants enrolled in an ongoing prospective study of community-dwelling elders. Four SNPs from ESR1 and four from ESR2 were analyzed. We measured cognitive function with the Modified Mini-Mental Status Examination (3MS) at baseline and biannually; cognitive impairment was defined as a decline of five or more points over 4 years. We calculated odds of developing cognitive impairment across SNPs using gender-stratified logistic regression and adjusted analyses for age, education, baseline 3MS score and in addition for race.


RESULTS
One thousand three hundred and forty-three women (mean age 73.4) and 1184 men (mean age 73.7) comprised our cohort. Among women, after multivariate adjustment, two of the ESR1 SNPs (rs8179176, rs9340799) and two of the ESR2 SNPs (rs1256065, rs1256030) were associated with likelihood of developing cognitive impairment, although the association for rs8179176 was of trend level significance. In men, one of the ESR1 SNPs (rs728524) and two of the ESR2 (rs1255998, rs1256030) were associated with cognitive impairment. Further adjustment for race attenuated the results somewhat. There was no association between any ESR SNP and level of bioavailable estradiol but testosterone level did vary among two of the SNPs (p<0.05).


CONCLUSIONS
We found that among non-demented community elders, several SNPs in the ESR1 and ESR2 genes were associated with risk of developing cognitive impairment. These findings suggest that estrogen receptor genetic variants may play a role in cognitive aging.
Yaffe
Kristine
K
Department of Psychiatry and Neurology, School of Medicine, San Francisco, CA 94121, USA. Kristine.yaffe@ucsf.edu
Lindquist
Karla
K
Sen
Saunak
S
Cauley
Jane
J
Ferrell
Robert
R
Penninx
Brenda
B
Harris
Tamara
T
Li
Rongling
R
Cummings
Steven R
SR
D000368:Aged; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015331:Cohort Studies; D019610:Cytoprotection / Q000235:genetics; D004252:DNA Mutational Analysis; D047629:Estrogen Receptor beta / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
D047629:Estrogen Receptor beta; D004967:Estrogens; D011960:Receptors, Estrogen