Admin Supplement - Prevention of Alzheimer's disease in women: risks and benefits of hormone therapy

摘要 使用外源性激素治疗与更年期相关的神经症状以及 老年性疾病，如阿尔茨海默病(AD)，是有争议的。这场争论是由几个 临床试验包括妇女健康倡议(WHI)记忆研究(WHIMS)、认知的WHI研究 老龄化(WHISCA)，对年轻女性记忆的WHI研究(异想天开)，早期干预与晚期干预 绝经期激素治疗(HT)不能预防痴呆症的雌激素治疗(精英)，或者 痴呆症增加和认知不良影响。总而言之，这些研究的结果表明，HT 如果在绝经前后的关键时间窗内使用，可能有效，但在老年女性中无效。MT的类型 接触途径(即口服结合雌激素[oCEE]与透皮雌激素[TE2])也很重要 还有一些研究，如Kronos早期雌激素预防研究(Keep)，这是一项双盲随机临床试验 试验，调查了这些MT在绝经开始后3年内服用时对认知的影响。 羟色胺反应的变化可能与药物动力学和生物利用度有关 注射外源性雌激素。例如，在Keep队列中，两个基因的遗传变异 编码参与雌激素代谢和运输的两种不同蛋白质：SULTA1和SLCO1B1 分别与更年期潮热的严重程度有关。在这项补充拨款中，目标是 在Keep Continue研究中调查女性的遗传变异，该研究旨在调查这些影响 在服用羟色胺13年后，高血压及其与AD的任何相关性。基因分析将是 扩展到包括参与雌激素药代动力学的其他基因以及编码这些基因的基因 参与雌激素信号/药效途径的蛋白质，可能影响对激素的反应 与认知、大脑结构和功能相关的治疗。这项研究的结果将导致更好的 了解遗传变异对雌激素药代动力学和药效途径的影响， 洞察羟色胺治疗AD的争议，引导个体化发展 阿尔茨海默病的治疗方法。

ABSTRACT The use of exogenous hormones to treat the neurological symptoms associated with menopause as well as diseases of aging such as Alzheimer's disease (AD) is controversial. This controversy arose from several clinical trials including the Women's Health Initiative (WHI) memory study (WHIMS), the WHI study of cognitive aging (WHISCA), the WHI study of memory in younger women (WHIMSY), Early vs Late Intervention Treatment with Estrogen (ELITE) where menopausal hormone therapy (HT) either did not prevent dementia, or increased dementia and adverse cognitive effects. Collectively, these results of these studies suggest that HT may be effective if used within a critical window around menopause but not in in older women. The type of MT and route of exposure (i.e. oral conjugated equine estrogen [oCEE] vs. transdermal E2 [tE2]) are also important and studies such as the Kronos Early Estrogen Prevention Study (KEEPS), a double blind randomized clinical trial, have investigated effects of these MT on cognitive when given within 3 years of the onset of menopause. Variation in responses to HT may be related to pharmacokinetics and bioavailability associated with administering an exogenous estrogen. For example, in the KEEPS cohort, genetic variants of two genes encoding two different proteins involved in estrogen metabolism and transport i.e. SULTA1 and SLCO1B1 respectively, were associated with severity of menopausal hot flashes. In this supplemental grant, the goal is to investigate genetic variation in women in the KEEPS continuation study, which aims to investigate the effects of HT and any correlations to AD, thirteen years after the administration of HT. The genetic analysis will be expanded to include additional genes involved in estrogen pharmacokinetics, as well as those encoding proteins involved in estrogen signaling/pharmacodynamic pathways, which may impact response to hormone therapy in relation to cognition and brain structure and function. The results from this study will lead to a better understanding of the impact of genetic variation in estrogen pharmacokinetic and pharmacodynamic pathways, provide insight to the controversy of HT for AD therapy, and lead the way to developing individualized treatment approaches to AD.