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

管理补充 - 预防女性阿尔茨海默病：激素治疗的风险和益处

• 批准号: 10163429
• 负责人: CAREY E GLEASON
• 金额: $ 41.56万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163429
• 关键词: Affect; Age of Onset; Aging; Alkanesulfonates; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid beta-Protein; Aromatase; Benefits and Risks; Biological Availability; Biology; Blood; Blood Vessels; Brain; CYP1A2 gene; CYP3A4 gene; CYP3A5 gene; Cause of Death; Clinical Trials; Cognition; Cognitive; Cognitive aging; Cohort Studies; Conjugated Equine Estrogens; Data; Dementia; Disease; Dose; Double-Blind Method; Drug Kinetics; ESR1 gene; ESR2 gene; Enrollment; Enzymes; Estradiol; Estrogen Metabolism; Estrogen Receptors; Estrogen Therapy; Estrogens; Etiology; Exogenous Hormone Therapy; Formulation; GRIP1 gene; Genes; Genetic Variation; Genotype; Goals; Grant; Health; Healthcare; Hepatocyte; Hormone use; Hormones; Hot flushes; Individual; Intervention; Lead; Lesion; Link; Magnetic Resonance Imaging; Measures; Memory; Menopausal Symptom; Menopause; Metabolism; Moods; NCOA1 gene; Neurologic; Neurologic Symptoms; Night Sweating; Oral; Outcome; Ovarian aging; Pathologic; Pathway interactions; Perimenopause; Pharmacodynamics; Placebo Effect; Placebos; Positron-Emission Tomography; Postmenopause; Prevention; Proteins; Randomized; Randomized Clinical Trials; Reporting; Safety; Severities; Signal Pathway; Signal Transduction; Sleep disturbances; Sleeplessness; Source; Structure; Sulfate; TREM2 gene; Thick; UGT1A1 gene; Variant; White Matter Hyperintensity; Woman; Women' s Health; abeta deposition; age related; apolipoprotein E-4; associated symptom; base; cognitive performance; enzyme activity; estrogen sulfate; exposure route; genetic analysis; genetic variant; hormone therapy; imaging biomarker; individual variation; individualized medicine; insight; older women; personalized medicine; pharmacokinetics and pharmacodynamics; physical symptom; protein function; receptor; response; response biomarker; sulfotransferase; young woman

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.

抽象的 使用外源激素治疗与更年期相关的神经系统症状以及 阿尔茨海默病（AD）等衰老疾病是有争议的。此次争议是由多方引发的 临床试验包括女性健康倡议 (WHI) 记忆研究 (WHIMS)、WHI 认知研究 衰老 (WHISCA)、年轻女性记忆力 WHI 研究 (WHIMSY)、早期干预与晚期干预 雌激素治疗（ELITE），其中绝经期激素疗法（HT）不能预防痴呆，或 增加痴呆症和不良认知影响。总的来说，这些研究的结果表明 HT 如果在更年期前后的关键窗口内使用可能会有效，但对老年女性则无效。 MT 类型 和暴露途径（即口服结合马雌激素 [oCEE] 与透皮 E2 [tE2]）也很重要 以及 Kronos 早期雌激素预防研究 (KEEPS) 等研究，这是一项双盲随机临床研究 一项试验研究了在绝经开始后 3 年内服用这些 MT 对认知的影响。 对 HT 反应的变化可能与药代动力学和生物利用度有关 给予外源性雌激素。例如，在 KEEPS 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，即 SULTA1 和 SLCO1B1 分别与更年期潮热的严重程度相关。这笔补充赠款的目标是 在 KEEPS 持续研究中调查女性的遗传变异，该研究旨在调查其影响 HT 治疗 13 年后，以及与 AD 的任何相关性。遗传分析将是 扩展到包括与雌激素药代动力学有关的其他基因，以及编码的基因 参与雌激素信号/药效途径的蛋白质，可能会影响对激素的反应 与认知和大脑结构和功能有关的治疗。这项研究的结果将带来更好的结果 了解遗传变异对雌激素药代动力学和药效学途径的影响， 为 HT 治疗 AD 的争议提供见解，并引领个体化治疗的发展之路 AD 的治疗方法。

项目成果

The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

Kronos 早期雌激素预防研究 (KEEPS)：我们学到了什么？

• 发表时间: 2019-04-01
• 作者: Miller, Virginia M;Naftolin, Fredrick;Asthana, Sanjay;Black, Dennis M;Brinton, Eliot A;Budoff, Matthew J;Cedars, Marcelle I;Dowling, N Maritza;Gleason, Carey E;Hodis, Howard N;Jayachandran, Muthuvel;Kantarci, Kejal;Lobo, Rogerio A;Manson, JoA
• 通讯作者: Manson, JoA