Epidemiology of menopause and dementia in Down syndrome

描述（由申请人提供）：本项目的总体目的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征（DS）女性认知能力下降和阿尔茨海默病（AD）风险的贡献。先前在一般人群中的研究表明，绝经后雌激素水平的急剧下降可能在AD的病因学中起重要作用。在患有DS的女性中，绝经开始的平均年龄为46岁，AD开始的平均年龄为50-55岁。因此，在DS女性中，绝经和AD之间的短时间间隔提供了一个独特的机会，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。我们推测，具有与生物可利用E2水平降低相关的基因型的女性将具有更早的发病和AD的风险增加。在我们目前对DS女性的研究中，我们进行了几项关键观察：（a）绝经年龄较早与DS女性AD的早期发作相关;（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的早期发作和风险增加相关。我们现在建议通过新的实验室研究扩大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女性患者进行一项为期5年的纵向研究，基线时年龄为40-59岁，每隔18个月随访一次。我们将研究5个候选基因：ER α，ER β，CYP 17，CYP 19和HSD 17 B1。我们将确定ER α（P和X）、ER β（G）、Cyp 17（等位基因A2），CYP 19（TTTA重复长度）和HSD 17 B1（A等位基因）（1）与系统性性腺激素和类固醇激素的基线水平和随时间变化率的差异相关;（即血清雌二醇、生物可利用雌二醇、雌酮、性激素结合球蛋白、脱氢表雄甾酮、促卵泡激素和孕酮）;（2）是记忆力和相关认知功能下降速度的预测因素;（3）与AD的早期发病或风险增加有关。拟议的研究将阐明与雌激素变化有关的生物学机制。

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.