Insulin, Cognitive Impairment and Alzheimer's Disease

描述（由申请人提供）：尽管阿尔茨海默病（AD）有多种病因，但所有AD病例都具有脑中淀粉样β肽（Abeta）斑块和神经元缠结的神经病理学标志，表明AD发病机制可能存在共同途径。载脂蛋白E4（ApoE4）已被确定为晚发性AD的主要危险因素，但约50%的病例不携带ApoE4等位基因。有趣的是，高胰岛素血症被发现与AD病例在ApoE 4影响的情况下。37%的AD受试者患有葡萄糖耐量受损，可能还具有升高的血浆胰岛素，而在相同人群中非AD受试者的比例为19.9%。拟议研究的主要假设是，高胰岛素血症是不存在ApoE4的迟发性AD的另一个风险因素。胰岛素和AB是AD病理学的主要成分，具有共同的生化特征。两者都是具有淀粉样蛋白生成特性的短肽，并且都被共同的蛋白酶胰岛素降解酶（IDE）降解。为了探索高胰岛素血症如何导致AD的机制，我们的次要假设是，在高胰岛素血症中，胰岛素与AB竞争IDE，增加AB的量，从而导致AD病理学。为了将候选人对IDE和ABeta的基础研究转化为对AD的临床研究，该提案提出了一个多方面的合作研究。通过在波士顿招募1600名居家老人的项目中合作，受试者将可用于评估胰岛素水平与认知障碍和AD之间的关系。不携带ApoE4且未接受胰岛素治疗的受试者将符合研究标准。将在不存在ApoE4的情况下评价空腹血浆胰岛素水平与认知损害之间的定量相关性。将对473例受试者子集进行临床检查和MRI扫描，以评价AD与非AD受试者中高胰岛素血症的相关性。 高胰岛素血症存在于一些但不是所有的2型糖尿病病例中。由于高胰岛素血症而不是单独的2型糖尿病可能是AD的相关风险因素，因此还将分析AD与高胰岛素血症vs. 2型糖尿病的相关性。我们将确定胰岛素水平和认知功能是否与Aa水平和IDE活性相关。这项研究的结果应该为确定胰岛素升高是否会增加前瞻性研究中AD的发病率提供依据。

DESCRIPTION (provided by applicant): Despite the fact that there are multiple etiologies of Alzheimer's disease (AD), all AD cases share the neuropathological hallmark of amyloid-Beta peptide (Abeta) plaques and neurofibrillary tangles in brain, indicating a possible common pathway of AD pathogenesis. Apolipoprotein E4 (ApoE4) has been identified as a major risk factor of late-onset AD, but approximately 50% of cases do not carry the ApoE4 allele. Interestingly, hyperinsulinaemia is found to be associated with AD cases in the absence of ApoE 4 influence. 37% of AD subjects suffer from impaired glucose tolerance, presumably also having elevated plasma insulin, compared to 19.9% of non-AD subjects in the same population. The major hypothesis of the proposed study is that hyperinsulinaemia is another risk factor of late-onset AD in the absence of ApoE4. Insulin and AB, the major component in AD pathology, share biochemical features. Both are short peptides with amyloidogenic properties, and both are degraded by a common protease, insulin-degrading enzyme (IDE). To explore the mechanism of how hyperinsulinaemia might contribute to AD, our secondary hypothesis is that in hyperinsulinaemia insulin competes with AB for IDE, increasing the amount AB and thus causing AD pathology. To translate the candidate's basic research on IDE and ABeta into clinical research on AD, this proposal presents a multi-faceted and collaborative study. By collaborating in a project that will recruit 1600 homebound elderly in Boston, subjects will be available to evaluate the relationship between insulin levels with cognitive impairment and AD. Subjects who do not carry ApoE4 and have not received insulin treatment will meet study criteria. Quantitative correlation will be evaluated between fasting plasma insulin level and cognitive impairment in the absence of ApoE4. Clinical examination and MRI scans will be performed on a subset of 473 subjects to evaluate the association of hyperinsulinaemia in AD vs. non-AD subjects. Hyperinsulinaemia is present in some but not all cases of type 2 diabetes. Because hyperinsulinaemia rather than type 2 diabetes alone may be the relevant risk factor of AD, the association of AD with hyperinsulinaemia vs. type 2 diabetes will also be analyzed. We will determine whether levels of insulin and cognitive function are correlated with Aa levels and IDE activity. Results from this study should provide a rationale to determine if elevated insulin increases the incidence of AD in a prospective study.