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

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