Lack of an association of estrogen receptor alpha gene polymorphisms and transcriptional activity with Alzheimer disease

Background: Long-term cognitive decline in postmenopausal women is associat ed with aging and Alzheimer disease (AD). Estrogen replacement therapy has been reported to reduce the risk of developing AD. The distribution of estr ogen receptors (ERs) in neurons overlaps that of the brain neurons known to develop AD. Estrogen increases the secretion and metabolism of amyloid pre cursor protein, may help synapse formation, and is reported to protect neur ons from toxins. Restriction fragment length polymorphisms: (RFLPs) of the ER alpha gene at intron 1 and exon 2 were associated with a low bone minera l: density in postmenopausal women and also with AD in a Japanese populatio n. Objective: To determine whether ER alpha gene polymorphisms are associated with transcriptional activity and AD. Methods: A luciferase reporter assay analyzed enhancer activity of the ER a lpha gene at intron 1 and exon 2. This activity was evaluated according to the RFLPs. The RFLPs of the ER alpha gene were determined in Japanese patie nts clinically diagnosed as having AD, white patients diagnosed as having A D at autopsy, and corresponding healthy control subjects. The RFLPs were al so evaluated for the contribution of the ER alpha gene RFLPs to AD. Results: We found weak (about 2-fold) enhancer activity of the ER alpha gen e, which differed among RFLPs. Although there were racial differences in th ese polymorphisms, we could not confirm the previously reported association between ER alpha, gene polymorphisms and AD. Conclusion: Regulatory element of the ER alpha gene was found in intron 1, but we found no association between ER alpha gene polymorphisms and AD.