Peripheral and brain levels of advanced glycation end products AGEs and incident Alzheimers disease and neuropathology

摘要 治疗阿尔茨海默病(AD)和认知能力下降是我们老龄化人口的健康优先事项。 令人信服的小规模研究表明，晚期糖基化的饮食、血清和大脑水平升高 终末产物(AGEs)是一组葡萄糖衍生化合物，可导致认知障碍和 老年时脑部病理增加。然而，由于缺乏对大量油井的尸检研究- 老年人的特征使得很难获得将大脑年龄与认知障碍联系起来的证据 老年人以及大脑年龄是否在饮食和血清AGEs与认知之间起中介作用。这些知识上的差距 阻碍以年龄为基础的治疗方法的发展，以减轻日益增长的AD和认知负担 拒绝。 为了填补这些空白，这项提议的总体目标是测试大脑年龄与 与AD和其他神经病理有关的老年人认知障碍，以及饮食 血清AGE与脑年龄相关。为了达到这些目标，我们将招募700个社区居民 来自Rush Memory and Aging Project(MAP，R01AG17911)的无临床痴呆症的老年人 在死亡时接受年度检测和有组织的尸检。这项研究提出了一个全面评估 AGEs水平量化饮食、血清和大脑AGEs水平。此外，我们还将获取和摘录小说 补充现有临床数据和传统尸脑的尸脑MRI指标 组织病理学。这项全面的大规模研究将提供证据，证明大脑年龄水平 与老年人认知受损有关，2)确定将大脑年龄与 3)测试大脑年龄是否在饮食和血清年龄与认知之间的联系中起到中介作用。这些 数据对于开发针对老年认知障碍的治疗方法至关重要。因此，这些数据 有可能减轻日益增长的认知障碍负担并影响大脑健康 在我们老龄化的人口中，有数百万美国人。

ABSTRACT Treatment's for Alzheimer's disease (AD) and cognitive decline is a health priority in our aging population. Compelling small scale studies suggest that elevated dietary, serum and brain levels of Advanced Glycation End products (AGEs), a group of glucose-derived compounds, contribute to cognitive impairment and increased brain pathology in old age. However, the scarcity of autopsy studies from large numbers of well- characterized older adults has made it difficult to obtain evidence linking brain AGEs with impaired cognition in older adults and whether brain AGEs mediate diet and serum AGEs with cognition. These gaps in knowledge impede the development of treatments based on AGEs to decrease the growing burden of AD and cognitive decline. To fill these gaps, the overall goal of this proposal is to test the hypothesis that brain AGEs are related to impaired cognition in older adults through an association with AD and other neuropathologies, and that dietary and serum AGEs are related to brain AGEs. To achieve these aims, we will enroll 700 community-dwelling older adults without clinical dementia from the Rush Memory and Aging Project (MAP, R01AG17911) who undergo annual testing and structured autopsy at death. This study proposes a comprehensive assessment of AGEs levels quantifying dietary, serum and brain AGEs levels. In addition, we will obtain and extract novel post-mortem brain MRI indices which complement available clinical data and traditional post-mortem brain histopathology. This comprehensive large-scale study will 1) provide evidence that brain AGEs levels are related to impaired cognition in older adults, 2) identify the key neuropathologies linking brain AGEs with cognition and 3) test if brain AGEs mediate the association of dietary and serum AGEs with cognition. These data are crucial for developing treatments targeting AGEs for late-life cognitive impairment. Thus, these data have the potential to decrease the growing burden of cognitive impairment and affect the brain health of millions of Americans in our aging population.