Progression from Amnesic Mild Cognitive Impairment to Alzheimer’s Disease: <i>ESR1</i> and <i>ESR2</i> Polymorphisms and <i>APOE</i> Gene

Abstract

Background: Many genes have been studied to determine how they might be involved in Alzheimer’s disease (AD). Estrogens have a protective effect in the central nervous system. The mechanisms of action of estrogens are mediated by two estrogen receptors (ERs), ERα and ERβ. Thus, these genes could also play a role in the progression of amnesic mild cognitive impairment (MCIa) to AD. The aim of this study was to examine the role of ER single nucleotide polymorphisms (SNPs) as a risk factor for MCIa, as well as the interaction with apolipoprotein E (APOE) Ε4 in the progression to AD. Methods: 79 MCIa patients and 138 healthy controls were analyzed. SNPs were genotyped via restriction fragment length polymorphisms and real-time PCR, RT-PCR or RT-PCR (TaqMan) assays. Results: There is a lack of association between MCIa patients who converted to AD and ER SNPs. APOE Ε4 allele is an independent risk factor of MCIa (OR = 1.86; 95% CI = 1.02–3.38, p = 0.042) with a high prevalence in converted subjects. APOE Ε4 is able to predict the progression from MCIa patients to AD (OR = 2.55; 95% CI = 1.20–5.42, p = 0.015). Conclusions: The presence of the APOE Ε4 allele, and not the alleles of ER SNPs, is a risk factor for MCIa. Furthermore, APOE genotype seems to predict the conversion from MCIa to AD.

Estrogen receptor β in Alzheimer’s disease: From mechanisms to therapeutics

“…A cohort study performed in 79 amnestic mild cognitive impairment (MCIa) patients and 144 healthy controls examined the association between the ERβ SNP rs4986938 and the development of MCIa as well as the interaction between rs4986938 and APOE4 in the progression of AD. The investigators reported that the presence of the APOE4 allele, and not the alleles of the ERβ SNP, is a risk factor for the conversion of MCIa to AD (Elcoroaristizabal Martin et al, 2011). Later, the same investigators conducted a case-control study that examined the association between rs4986938 and the risk of MCIa or AD and no association was found (Fernandez-Martinez et al, 2013).…”

“…One major factor that may have contributed to the disparities among studies could be the composition of the study population. One common feature shared in 4 of the 5 reports that failed to find an association is that those studies were all based on a mixed population of both genders (Elcoroaristizabal Martin et al, 2011; Fernandez-Martinez et al, 2013; Ryan et al, 2014). In contrast, of the 8 studies that showed a positive result, 7 studies were either conducted only in women (Dresner-Pollak et al, 2009; Janicki et al, 2014; Luckhaus et al, 2006; Ryan et al, 2013; Zhao et al, 2011c) or stratified by gender (Pirskanen et al, 2005; Yaffe et al, 2009), and all showed a significant association between ERβ polymorphisms and AD susceptibility in women.…”

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

“…Some studies show such a relationship while others do not. In the study of Elcoroaristizabal et al [32] an association between the APOE ε4 allele and amnesic mild cog-nitive impairment was found while no relation to cognition was observed for ESR1 polymorphisms in elderly women. In contrast, in the same study the polymorphisms within the ESR2 gene were associated with lower cognitive performance [30].…”

The etiological effect of a new low-frequency ESR1 variant on Mild Cognitive Impairment and Alzheimer’s Disease: a population-based study

“…As one of NR family member, estrogen receptor α (Erα, P03372), encoded by the ERS1 gene, is highly expressed in brain regions especially the hippocampus and hypothalamus which are associated with memory and cognitive performance [ 25 – 27 ]. ERα is activated by binding with estrogen and estrogen-ERs has been proposed to partake in cholesterol metabolism and Aβ accumulation in brains from LOAD patients [ 28 ].…”