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

Abstract

BackgroundGenetic variation in the estrogen receptor (ESR) may be associated with the incidence of Alzheimer's disease (AD), but this association could be modified by genetic and environmental factors.MethodsThe association between five ESR α (ESR1) and β (ESR2) polymorphisms with 7‐year dementia incidence was examined among 6959 older men and women from the Three City Study using multivariate‐adjusted Cox regression models with delayed entry. Gender, the apolipoprotein E (APOE) ε4 allele, and hormone treatment were considered as potential effect modifiers of this association.ResultsAmong women, the CC genotype of ESR1 rs2234693 was specifically associated with a small increased risk of AD (adjusted hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.03–2.28, P = .03). However, women with this genotype had a substantially increased risk of AD associated with the APOE ε4 allele (adjusted HR: 3.24, 95% CI: 1.81–5.79 for women rs2234693 CC; compared with HR: 1.87, 95% CI: 1.37–2.56 for all women). There was also evidence of a nominally significant interaction between the ESR1 and ESR2 polymorphisms on the risk of all dementias (P = .04). Hormone treatment did not modify these associations, and there were no significant associations in men.ConclusionsAlthough there was only weak support for a gender‐specific association between the common ESR1 rs2234693 polymorphism and AD, this polymorphism may act as an effect modifier, modifying the association between an ESR2 polymorphism and dementia, as well as the risk of AD associated with the APOE ε4 allele.

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

“…However, significant associations with the ERβ polymorphism, rs1256049, were identified including an increased risk of substantial decline in visual memory, psychomotor speed, and on the incidence of MCI (Ryan et al, 2013). Further analysis indicated that, in support of the initial finding of a significant interaction between ERα and ERβ polymorphisms and the risk for AD (Lambert et al, 2001), the association between ERβ polymorphism and AD appeared to be modified by ERα polymorphism (Ryan et al, 2014). Interestingly, the same study showed a slight association between the minor allele of the ERβ SNP, rs4986938, and a decreased risk of decline in psychomotor speed (Ryan et al, 2013).…”

Age, APOE and sex: Triad of risk of Alzheimer’s disease

“…Estrogen receptors play a key and contrasting role in regulation of ApoE gene and protein expression (33) and risk of AD(141). ERα up-regulated ApoE mRNA and protein expression whereas in contrast, ERβ down-regulated ApoE mRNA and protein expression(33).…”

“…These data suggest that use of ER-selective ligands could provide therapeutic benefit to reduce the risk of AD by increasing ApoE expression in ApoE 2 or 3 allele carriers and decreasing ApoE expression in ApoE4 allele carriers. Polymorphisms in both estrogen receptor alpha (rs4986938) and estrogen receptor β (rs2234693) have been associated with increased risk of dementia and AD (141). …”

Estrogen: A master regulator of bioenergetic systems in the brain and body

“…A recent study proposed that one dominant negative splice variant, ERβ2, may mediate differential responses to E 2 treatment early and late after ovariectomy (OVX) in rats, such that only if estrogen treatment is initiated early after OVX is it able to prevent induction of the dominant negative ERβ2 variant (Wang et al, 2012). In addition to splice variants, there are several ERα polymorphisms that increase the risk of Alzheimer’s disease (AD) specifically in women, particularly when associated with the APOE ε4 allele (Ryan et al, 2013). …”