Association of Estrogen Receptor α (ESR1) <i>Pvu</i>II and <i>Xba</i>I Polymorphisms with Sporadic Alzheimer’s Disease and Their Effect on Apolipoprotein E Concentrations

Abstract

Background: Many studies have shown that estrogen replacement therapy may improve cognitive function in women and reduce the risk of Alzheimer’s disease (AD). Because most of the estrogen neuroprotective effect is mediated by receptors, we studied the associations between estrogen receptor α (ESR1) polymorphisms (PvuII and XbaI) and AD, and their interactions with apolipoprotein E (APOE) polymorphism and plasma levels. Methods: ESR1 genotypes and APOE plasma concentrations were determined in a sample of AD patients and controls. Results: ESR1 PP and XX genotypes were associated with an increased risk for AD only in males (OR = 3.6, 95% CI = 1.2–10.9) and conferred a relevant additional risk of AD to subjects also carrying APOE e*4 allele (OR = 13.3, 95% CI = 1.7–103.6). Mean APOE concentrations were lower in AD patients; the lowest levels were observed in male patients carrying PP and/or XX genotypes (p = 0.006) and in patients carrying PP and/or XX genotypes together with the e*4 allele (p = 0.003). In AD women, ESR1 PP and XX genotypes were also associated with lower MMSE values (p = 0.0007). Conclusion: The present data suggest that the involvement of ESR1 polymorphisms in AD onset is mediated by the regulation of apoE expression. ESR1 polymorphisms are also associated with a faster cognitive decline in the women AD patients.

Estrogen receptor polymorphisms and incident dementia: The prospective 3C study

“…Across all women, the Apoe-ε4 allele was associated with a highly significant 1.9 times increased risk (p<0.0001), however in women with the CC genotype, the risk of AD with the Apoe-ε4 allele increased to 3.2-fold (p<0.0001). This observation is supported by findings from two case-control studies [8,9], which grouped participants based on their ESR1 and ApoE-ε4…”

“…The direction of these associations is supported by a majority of significant case-control studies [8][9][10][11]37], although several prior studies have reported larger effect sizes in smaller samples. These differences may be partly explained by the populations studied, as the majority of significant findings have been found in Japanese populations [10,11,37].…”

“…The a priori interactions that were considered in this analysis were based on previous reports in the literature. This included an interaction between ESR1 and ESR2 polymorphisms [21] and the potential for ESR polymorphisms to modify the association between the Apoe-ε4 allele and the risk of AD [9,11]. We also examined potential interactions with hormone treatment, as it has been shown to modify the association between ESR and other health outcomes [34][35][36], but no prior study has examined whether it can modify the risk of dementia.…”

“…As only the second prospective study to be undertaken, we aim to help clarify previous findings, while also investigating prospectively for the first time, potential associations with ESR2 polymorphisms. Based on previous findings from relatively small case-control studies we also investigated a priori interactions between ESR1 and ESR2 receptors on the risk of dementia [21], and the possibility that ESR polymorphisms could further increase the risk of AD associated with the apolipoprotein E (ApoE) ε4 allele [9,11].…”

“…Some of these studies have reported that AD patients had a significantly higher frequency of the minor C and G alleles of rs2234693 and rs9340799 respectively [8][9][10][11], yet other studies have found no significant associations [12][13][14] or even reverse associations [15,16]. Meta-analyses conducted a few years ago found a small but significant association between the minor alleles of these polymorphisms and an increased risk of AD (OR~1.2) [17,18], however this is not supported by the most recent metaanalysis on the Alzheimer's Research Forum (http://www.alzgene.org).…”