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Lack of an Association of Estrogen Receptor  Gene Polymorphisms and Transcriptional Activity With Alzheimer Disease
Hirofumi Maruyama, MD;
Hiromasa Toji, MD;
Charles R. Harrington, PhD;
Ken Sasaki, MD;
Yuishin Izumi, MD;
Tohru Ohnuma, MD;
Heii Arai, MD;
Minoru Yasuda, MD;
Chikako Tanaka, MD;
Piers C. Emson, PhD;
Shigenobu Nakamura, MD;
Hideshi Kawakami, MD, PhD
Arch Neurol. 2000;57:236-240.
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 ER 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 ER gene polymorphisms are associated with transcriptional activity and AD.
Methods A luciferase reporter assay analyzed enhancer activity of the ER gene at intron 1 and exon 2. This activity was evaluated according to the RFLPs. The RFLPs of the ER 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 ER gene RFLPs to AD.
Results We found weak (about 2-fold) enhancer activity of the ER gene, which differed among RFLPs. Although there were racial differences in these polymorphisms, we could not confirm the previously reported association between ER gene polymorphisms and AD.
Conclusion Regulatory element of the ER gene was found in intron 1, but we found no association between ER gene polymorphisms and AD.
From the Third Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan (Drs Maruyama, Toji, Izumi, Nakamura, and Kawakami); Department of Mental Health, University of Aberdeen, Aberdeen, Scotland (Dr Harrington); Kinoko Espoir Hospital, Okayama, Japan (Dr Sasaki); Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan (Drs Ohnuma and Arai); Hyogo Institute for Aging Brain and Cognitive Disorders, Hyogo, Japan (Drs Yasuda and Tanaka); and Alzheimer's Trust Research Center and Department of Neurobiology, The Babraham Institute, Cambridge, England (Dr Emson).
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