Ratnakumar Abhirami, Zimmerman Samuel E, Jordan Bryen A, Mar Jessica C
Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
Alzheimers Dement (N Y). 2019 Dec 9;5:906-917. doi: 10.1016/j.trci.2019.09.004. eCollection 2019.
Women are at increased risk for Alzheimer's disease (AD), but the reason why remains unknown. One hypothesis is that low estrogen levels at menopause increases vulnerability to AD, but this remains unproven.
We compared neuronal genes upregulated by estrogen in ovariectomized female rhesus macaques with a database of >17,000 diverse gene sets and applied a rare variant burden test to exome sequencing data from 1208 female AD patients with the age of onset < 75 years and 2162 female AD controls.
We found a striking overlap between genes upregulated by estrogen in macaques and genes downregulated in the human postmortem AD brain, and we found that estrogen upregulates the gene and that progesterone acts antagonistically to estrogen genome-wide. We also found that female patients with AD have excess rare mutations in the early menopause gene .
We show with genomic data that the menopausal loss of estrogen could underlie the increased risk for AD in women.
女性患阿尔茨海默病（AD）的风险增加，但其原因尚不清楚。一种假说认为，绝经后雌激素水平降低会增加患AD的易感性，但这一点尚未得到证实。
我们将卵巢切除的雌性恒河猴中由雌激素上调的神经元基因与一个包含超过17000个不同基因集的数据库进行比较，并对1208名发病年龄<75岁的女性AD患者和2162名女性AD对照的外显子测序数据进行罕见变异负担测试。
我们发现猕猴中由雌激素上调的基因与人类AD死后大脑中下调的基因之间存在显著重叠，并且我们发现雌激素上调了 基因，而孕酮在全基因组范围内对雌激素起拮抗作用。我们还发现，患有AD的女性患者在早发性绝经基因中存在过多的罕见突变。
我们通过基因组数据表明，绝经后雌激素的丧失可能是女性患AD风险增加的基础。
