Insulin, Cognitive Impairment and Alzheimer's Disease

描述(申请人提供)：尽管阿尔茨海默病(AD)的病因是多方面的，但所有AD病例都具有脑内淀粉样β蛋白(Abeta)斑块和神经原纤维缠结的神经病理特征，表明AD可能有一种共同的发病途径。载脂蛋白E4(ApoE4)已被认为是晚发性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缺乏ApoE4影响的AD病例有关。37%的AD受试者患有糖耐量受损，推测还存在血浆胰岛素升高，而同一人群中非AD受试者的这一比例为19.9%。这项拟议研究的主要假设是，高胰岛素血症是缺乏载脂蛋白E4的晚发性AD的另一个危险因素。胰岛素和AB是AD病理中的主要成分，具有共同的生化特征。两者都是具有淀粉样变性的短肽，都被一种常见的蛋白酶--胰岛素降解酶(IDE)降解。为了探讨高胰岛素血症在AD发病机制中的作用，我们的第二个假设是，在高胰岛素血症中，胰岛素与AB竞争IDE，使AB数量增加，从而导致AD病理。为了将候选人在IDE和ABETA方面的基础研究转化为AD的临床研究，本提案提出了一项多方面的合作研究。通过合作一个项目，将在波士顿招募1600名呆在家里的老年人，受试者将可以评估胰岛素水平与认知障碍和AD之间的关系。未携带载脂蛋白E4且未接受胰岛素治疗的受试者将符合研究标准。在缺乏载脂蛋白E4的情况下，将评估空腹血浆胰岛素水平与认知损害之间的定量相关性。临床检查和核磁共振扫描将在473名受试者中进行，以评估AD和非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型糖尿病患者中。由于高胰岛素血症而不是2型糖尿病可能是AD的相关危险因素，因此也将分析AD与高胰岛素血症与2型糖尿病的关系。我们将确定胰岛素水平和认知功能是否与AA水平和IDE活动相关。这项研究的结果应该为在前瞻性研究中确定胰岛素升高是否会增加AD的发病率提供理论依据。

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.