Epidemiology of menopause and dementia in Down syndrome

唐氏综合症更年期和痴呆的流行病学

• 批准号: 7475752
• 负责人: NICOLE SCHUPF
• 金额: $ 48.18万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475752
• 关键词: Adult; Age; Age-Years; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Anabolism; Apolipoprotein E; Basic Science; Bioavailable; Biological; Blood; CYP17A1 gene; CYP19A1 gene; Candidate Disease Gene; Cholesterol; Cognitive; Cox Proportional Hazards Models; DNA; Dementia; Deposition; Development; Down Syndrome; Epidemiology; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Estrone; Ethnic Origin; Etiology; Follicle Stimulating Hormone; General Population; Genes; Genetic; Genetic Polymorphism; Genotype; Gonadal Steroid Hormones; Hormones; Impaired cognition; Individual Differences; Institutes; Intake; Investigation; Laboratory Study; Length; Longitudinal Studies; Measures; Mediating; Memory; Menopause; Mental Retardation; Methods; Non-Steroidal Anti-Inflammatory Agents; Numbers; Obesity; Participant; Pathogenesis; Peptides; Performance; Plasma; Play; Postmenopause; Presenile Alzheimer Dementia; Progesterone; Program Research Project Grants; Prospective Studies; Range; Rate; Research; Research Personnel; Risk; Role; Sampling; Serum; Sex Hormone-Binding Globulin; Survival Analysis; Testing; Time; Variant; Woman; amyloid peptide; apolipoprotein E-4; cognitive function; cohort; disorder risk; early onset; epidemiology study; peptide A; programs; receptor function

DESCRIPTION (provided by applicant): The overall aim of this project is to investigate the contribution of polymorphisms in genes involved in estrogen biosynthesis and estrogen receptor function to rate of cognitive decline and risk of Alzheimer's disease (AD) in women with Down syndrome (DS). Prior studies in the general population suggest that the dramatic declines in estrogen levels following menopause may play an important role in the etiology of AD. Among women with DS, the average age at onset menopause is 46 and the average age at onset of AD is 50-55. Thus, in women with DS, the short interval between menopause and AD provides a unique opportunity to examine the influence of endogenous estrogen activity on disease risk in a prospective study. We hypothesize that women with genotypes associated with reduced levels of bioavailable E2 will have earlier onset and increased risk of AD. During our current study of women with DS, we have made several key observations: (a) earlier age at menopause was associated with earlier onset of AD in women with DS; (b) high levels of sex-hormone binding globulin and low levels of bioavailable estradiol were associated with earlier onset and increased risk of dementia. We now propose to expand our investigation of endogenous estrogen activity with new laboratory studies to identify genetic factors that may modify estrogen levels or estrogen activity and influence risk for AD. We will conduct a 5-year longitudinal study of in 336 women with DS, 40-59 years of age at baseline, followed at 18-month intervals. We will examine 5 candidate genes: ERalpha, ERbeta, CYP17, CYP19, and HSD17B1. We will determine whether polymorphisms in the genes for ERalpha (P and X), ERbeta (G), Cyp17 (Allele A2), CYP19 (TTTA repeat length) and HSD17B1 (A Allele) are (1) associated with differences in baseline levels and rates of change over time in systemic gonadal and steroid hormones; (i.e. serum estradiol, bioavailable estradiol, estrone, sex-hormone binding globulin, dehydroepiandrostcrone, follicle stimulating hormone and progesterone); (2) are predictors of the rate of decline in memory and related cognitive functions; and (3) are associated with earlier onset or increased risk of AD. The proposed studies will clarify biological mechanisms relating variations in estrogen to the development of AD.

描述（由申请人提供）：该项目的总体目标是研究参与雌激素生物合成和雌激素受体功能的基因多态性对唐氏综合症（DS）女性认知能力下降速度和阿尔茨海默病（AD）风险的影响。先前对普通人群的研究表明，绝经后雌激素水平的急剧下降可能在 AD 的病因学中发挥重要作用。在患有 DS 的女性中，绝经期的平均发病年龄为 46 岁，AD 的平均发病年龄为 50-55 岁。因此，对于患有 DS 的女性，绝经期和 AD 之间的短暂间隔提供了一个独特的机会，可以在前瞻性研究中检查内源性雌激素活性对疾病风险的影响。我们假设，具有与生物可利用 E2 水平降低相关的基因型的女性将更早发病并增加 AD 风险。在我们目前对患有 DS 的女性进行的研究中，我们得出了几项重要的观察结果：(a) 患有 DS 的女性更年期较早与 AD 较早发病有关； (b) 高水平的性激素结合球蛋白和低水平的生物可利用雌二醇与痴呆症的早期发病和风险增加有关。我们现在建议通过新的实验室研究来扩大对内源性雌激素活性的研究，以确定可能改变雌激素水平或雌激素活性并影响 AD 风险的遗传因素。我们将对 336 名 DS 女性进行一项为期 5 年的纵向研究，基线年龄为 40-59 岁，每隔 18 个月进行一次随访。我们将检查 5 个候选基因：ERalpha、ERbeta、CYP17、CYP19 和 HSD17B1。我们将确定 ERalpha（P 和 X）、ERbeta（G）、Cyp17（等位基因 A2）、CYP19（TTTA 重复长度）和 HSD17B1（A 等位基因）基因的多态性是否 (1) 与基线水平的差异以及全身性腺和类固醇激素随时间的变化率相关； (即血清雌二醇、生物可利用的雌二醇、雌酮、性激素结合球蛋白、脱氢表雄酮、卵泡刺激素和黄体酮)； (2) 是记忆力和相关认知功能下降速度的预测因素； (3) 与 AD 较早发病或风险增加有关。拟议的研究将阐明雌激素变化与 AD 发展相关的生物学机制。