Four SNPs in ESR2 were associated with an increased risk of AD, independent of APOE genotype. Among postmenopausal women, those who carried at least 1 copy of the T allele at rs4986938 were twice as likely to develop AD than those who carried the CC genotype. In addition, approximately 16kb away from rs4986938, a set of 3 contiguous SNPs was significantly associated with AD; these 3 SNPs were located within one haplotype block spanning approximately 7.8 kb (fig. ). Women with DS who carried the A allele at rs17766755, the G allele at rs4365213 or the A allele at rs12435857 had a 2-fold increased risk of AD, compared with women without these risk alleles. A haplotype-based Cox proportional hazards model continued to support that AGA carriers had a 2-fold risk of developing AD after adjusting for covariates.
Linkage disequilibrium patterns for SNPs in ESR2.
The association of these SNPs with an increased risk of AD was seen only among postmenopausal women. Among premenopausal or perimenopausal women, there were 5 who developed AD, 4 who were perimenopausal at baseline and 1 who was still menstruating at baseline. The mean age of the women who were premenopausal or perimenopausal was 42.9 (± 4.0) years; many of these women carrying high-risk alleles may have been too young to develop AD, attenuating the estimate of risk in the total group.
Polymorphisms or haplotypes in ESR2
have been associated with an increased risk for a number of estrogen-related disorders, including osteoporosis [47
], breast cancer, ovarian cancer [52
] and polycystic ovarian disease [61
]. ER-β is found in high concentrations in the hippocampus [51
], and its activation has been linked to synaptic plasticity and hippocampal-dependent cognition [13
]. Ovariectomized female Esr2–/–
knockout mice perform worse than wild-type mice in a spatial learning task and fail to show improvements in learning and memory when treated with estradiol [13
], suggesting that the effects of estrogen on hippocampal plasticity and memory may be mediated through ER-β [13
]. ER-β can couple to rapid signaling events and is required for estrogen-mediated neuroprotection [63
]. Thus, variants in ESR2
may influence cognition via a number of different pathways, including modification of hormone levels, changes in gene activity or changes in gene expression. However, specific pathways through which SNP activity modifies receptor function have not yet been identified.
Previous studies of the relationships of polymorphisms in ESR2
to the risk of AD have found a number of different SNPs to be associated with both increased and decreased risk. In 2 studies, SNPs in ESR2 (
rs1256065, rs1271573 and rs1256043) were associated with an increased risk for cognitive impairment or AD in women but not in men [29
], or were associated with an increased risk in men but not in women (rs1255998) [64
]. Another study found a cystosine-adenine repeat in ESR2
that was more strongly protective in men than in women [28
], and the Health ABC study found 1 SNP on ESR2
(rs1256030) that was associated with the development of cognitive impairment among both men and women [64
]. A diplotype including rs4986938 in the 3′ UTR region of ESR2
has been associated with the risk for AD in both men and women [31
], and rs4986938 has been associated with vascular dementia [32
]. Our finding of a 2-fold increase in the risk of developing AD among women carrying rs4986938 is consistent with prior studies [30
], but we did not see strong associations with rs1256065 or rs1256043, as seen previously [29
]. We have identified 3 new SNPS of ESR2
, rs17766755, rs4365213 and rs12435857, in introns seven (rs17766755) and six (rs4365213 and rs12435857). These SNPs are in high linkage disequilibrium and are associated with a 2-fold increased risk of AD.
Our study points to the role of genetic variants that influence estrogen receptor activity in modifying the risk for AD. Our results support and extend findings from prior studies suggesting that variants in ESR2 modify the risk for AD, both in the general population and in this high-risk group of women with DS. With the exception of rs1255998, all SNPs examined were intronic: rs1255998 is located in exon nine, but does not involve a coding change. The 12 additional SNPs were tested in noncoding (intron) regions and therefore they may not be the critical location of the pathological variants, but rather serve as markers for the critical region. Analysis of additional polymorphisms influencing estrogen biosynthetic pathways and estrogen receptor activity with additional and denser SNP coverage and correlative studies in brain cells will be useful to determine the contribution of estrogen variants to cognitive aging and a risk for AD.