Estrogen receptor beta polymorphisms and cognitive performance in women: associations and modifications by genetic and environmental influences

Abstract

Genetic and environmental risk factors contribute to the pathogenesis of Alzheimer's dementia. Besides known genetic risk factors like the apolipoprotein (APO) Eε4 allele, single nuclear polymorphisms (SNPs) of the estrogen receptors (ESRs) are candidate genetic risk factors, while air pollution represents an environmental risk factor for dementia. Effects of these risk factors and their interaction were investigated in the SALIA cohort of 834 non-demented elderly women. Cognitive function was assessed by the CERAD-plus test battery. Air pollution was estimated by land use regression (LUR) models. Genotyping was carried out for nine ESR1 and ESR2 SNPs and two ApoE SNPs. Carriers of minor ESR2 alleles showed significantly reduced cognitive performance in the CERAD total score with most pronounced deficits in semantic memory (rs1256062, rs10144225, and rs2274705) and executive function (rs1256062). The minor allele effects of ESR2 were stronger in carriers of APOEε4 for the cognitive domain 'executive function' (p value of interaction 0.023 for rs1256062). The investigated ESR1 SNPs were not associated with cognition. Furthermore, we found a significant gene-environment interaction between the ESR2 SNP rs1256062 and air pollution on cognition. Carriers of two major alleles of rs1256062 were more susceptible for an air pollution-induced decrease in performance of 'figure copying' than carriers of minor alleles (p value of interaction, e.g., 0.031 for PM). In conclusion, ESR2 but not ESR1 minor alleles were associated with lower cognitive performance in elderly women with an indication of a gene-gene interaction with APOEε4. We also found indications for gene-environment interactions of ESR2 with traffic-related air pollution exposure on cognitive performance.

Effect of interactions between APOE and ESR1 polymorphisms on cognitive functions in postmenopausal women

“…The study of Fernández-Martínez et al [13] showed increased risk of mild dementia and AD in the simultaneous presence of the APOE ε4 allele and polymorphic variants of both XbaI and PvuII polymorphisms within the ESR1 gene. Opposite to our study, Fehsel et al [11] found no relation of ESR1 polymorphisms and cognition, but minor variants of ESR2 polymorphisms had a significant impact on executive function in women carrying the APOE ε4 allele. In addition, the authors observed that air pollution increased the risk of cognitive decline in women.…”

“…It is also suggested that both ESR1 polymorphisms may have an impact on cognitive functioning [9,10]. However, there are also contrary results in the topic [11].…”

Clinical effects of air pollution on the central nervous system; a review

“…[23] For example, the Estrogen Receptor-2 (ESR2) allele is implicated in gene-environment interactions. [24]…”

Menopausal Hormone Therapy and the Mind: The Role of Hormone Replacement in the Prevention and Treatment of Cognitive Decline, Dementia, and Cognitive Dysfunction of Depression

“…Although a number of trials examined interaction effects of MHT with APOE genotype, none examined interactions with polymorphisms in other genes as part of the main study, and to our knowledge, no comprehensive examination of the relationship between MHT and genotypes of estrogen biosynthesis, metabolism, and transporter genes has been conducted. Polymorphisms of ERβ have been associated with increased risk of AD 122,123 and cognitive performance, 124 while polymorphisms in both estrogen biosynthesis genes, including COMT, CYP17, and CYP19A1, [125][126][127] and metabolism genes, including CYP11A1, 122 have been associated with AD. Genotypes of SULT1A1, an estrogen metabolism gene, and SLCO1B1, an estrogen transporter, affect estrogen levels and subtype balance; 120,128 other gene polymorphisms also likely influence MHT effects.…”