Freatures of Metabolic Syndrome and Risk for AD among Adults with Down Syndrome

所有40岁以上的唐氏综合征(DS)成年人在神经病理上都表现为阿尔茨海默病(AD)，部分原因是21号染色体上专有的DS区域内淀粉样前体蛋白基因的过度表达。虽然AD的发病一度被认为是随着DS变老的必然结果，但许多研究已经清楚地证明，尽管50岁以上的DS成年人有很大的AD发展风险，但风险似乎不是100%。实体个人 在这个种群中，差异是明显的，这表明应该有生物学因素导致这种异质性。然而，除了年龄、载脂蛋白E(APOE)基因、绝经年龄和胆固醇水平外，几乎没有发现其他危险因素。这项研究的总体目标是确定一系列症状，包括肥胖、血糖 代谢异常、血脂异常和高血压会影响成年DS患者的认知功能下降和AD的风险。肥胖导致胰岛素抵抗，从而导致高胰岛素血症，从而导致糖耐量异常和/或糖尿病、高血压、血脂异常和炎症。这种情况的汇合被称为新陈代谢综合征。代谢综合征的关键成分是高胰岛素水平(高胰岛素血症)。据报道，高胰岛素血症，以及代谢综合征的组成部分，在没有DS的人中，联合或单独与AD风险增加有关。 这个子项目的指导假设是代谢综合征的特征，特别是胰岛素抵抗/高胰岛素血症，与DS患者认知功能下降和AD发病的增加有关，正如在没有DS的人中观察到的那样。第二个目的是确定第二代抗精神病药物或他汀类药物的使用是否会影响认知能力下降和AD发病的风险，因为它们对代谢综合征的生理作用。胰岛素抵抗/高胰岛素血症和代谢综合征的其他方面可以通过适度的减肥、运动和药物干预来治愈。这项研究的结果可能为后续的临床干预提供可能的靶点，从而延迟或减少DS患者的AD发病率。治疗没有DS的AD患者的高胰岛素血症的临床试验已经进入第三阶段。

All adults with Down syndrome (DS) over 40 years of age exhibit Alzheimer's disease (AD) neuropathologically, due in part to the overexpression of the amyloid precursor protein gene within the obligate DS region on chromosome 21. While the onset of AD was once considered an inexorable result of growing old with DS, a number of studies have clearly established that although adults with DS over the age of 50 are at substantial risk for the development of AD, risk does not appear to reach 100%. Substantial individual differences are evident within this population, suggesting that there should be biological factors that contribute to this heterogeneity. However, with the exception of age, apolipoprotein E (APOE) genotype, age at menopause and cholesterol level, few additional risk factors have been identified. The overall aim of this study is to determine if a continuum of symptoms, including adiposity, glucose metabolism irregularities, dyslipidemia, and hypertension, influence cognitive decline and risk for AD in adults with DS. Adiposity leads to insulin resistance, which leads to hyperinsulinemia, which leads to glucose intolerance and/or diabetes, hypertension, dyslipidemia, and inflammation. This confluence of conditions has been referred to as the Metabolic syndrome. The key component of the Metabolic syndrome is high insulin levels (hyperinsulinemia). Hyperinsulinemia, as well as components of the Metabolic syndrome, in combination and individually, have been reported to be related to increased risk for AD in persons without DS. The guiding hypothesis of this subproject is that features of the Metabolic syndrome, and particularly insulin resistance/hyperinsulinemia, is related to an increase in cognitive decline and AD onset in DS, as has been observed in persons without DS. A secondary aim is to determine whether the use of secondgeneration antipsychotics or statins may influence the risk for cognitive decline and onset of AD as a function of their physiological action upon the Metabolic syndrome. Insulin resistance/hyperinsulinemia and other aspects of the Metabolic syndrome can be remediated through even modest weight loss, exercise and pharmaceutical intervention. Results from this study may suggest possible targets for subsequent clinical intervention leading to delay or reduction of AD incidence in persons with DS. Clinical trials to treat hyperinsulinemia in persons with AD without DS are already in phase III.