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