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.

摘要 使用外源性激素治疗与更年期相关的神经系统症状以及 老年性疾病如阿尔茨海默病（AD）是有争议的。这一争议源于几个 临床试验，包括妇女健康倡议（WHI）记忆研究（WHIMS），WHI认知研究， 老龄化（WHISCA），年轻女性记忆的WHI研究（WHIMSY），早期与晚期干预 雌激素治疗（ELITE），其中绝经期激素治疗（HT）不能预防痴呆，或 增加痴呆和不利的认知影响。总的来说，这些研究的结果表明HT 如果在更年期的关键窗口期使用，可能有效，但对老年妇女无效。MT类型 和暴露途径（即口服结合马雌激素[oCEE]与经皮E2 [tE 2]）也很重要 和研究，如Kronos早期雌激素预防研究（KEEPS），一项双盲随机临床研究， 试验，研究了这些MT对认知的影响，当绝经期开始后3年内给予。 对HT反应的变化可能与药物动力学和生物利用度有关， 施用外源性雌激素。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转运的两种不同蛋白质，即SULTA 1和SLCO 1B 1 与绝经期潮热的严重程度相关。在这项补充拨款中，目标是 在KEEPS继续研究中调查女性的遗传变异，该研究旨在调查 在服用HT后的13年内，HT和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，以及那些编码 参与雌激素信号传导/药效学途径的蛋白质，可能影响对激素的反应 治疗与认知和大脑结构和功能有关。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学途径的影响， 为HT治疗AD的争议提供了见解，并为开发个体化治疗提供了方向。 治疗AD的方法