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

摘要 阿尔茨海默病（AD）和认知能力下降的治疗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，饮食、血清和大脑中晚期糖基化水平的升高 终产物（AGEs）是一组葡萄糖衍生化合物，可导致认知障碍， 老年人大脑病变增加。然而，缺乏大量的尸检研究， 老年人的特征使得很难获得证据将大脑AGEs与认知受损联系起来， 老年人和大脑AGEs是否介导饮食和血清AGEs与认知。这些知识上的差距 阻碍了基于AGEs的治疗方法的发展，以减少AD和认知功能障碍日益增加的负担。 下降 为了填补这些空白，这项提案的总体目标是检验大脑AGEs与以下假设有关： 通过与AD和其他神经病理学的关联，老年人的认知受损， 血清AGEs与脑AGEs相关。为了实现这些目标，我们将招收700名社区居民， 来自拉什记忆和衰老项目（MAP，R01AG17911）的无临床痴呆的老年人， 每年进行一次检查，并在死亡时进行结构化尸检。本研究提出了一个全面的评估， AGEs水平定量饮食，血清和大脑AGEs水平。此外，我们将获得并提取新的 死后脑部MRI指标，补充现有临床数据和传统死后脑部 组织病理学这项全面的大规模研究将提供证据，证明大脑AGEs水平是 与老年人认知受损有关，2）确定大脑AGEs与 3）测试脑AGEs是否介导饮食和血清AGEs与认知的关联。这些 数据对于开发针对晚期认知障碍的AGEs治疗至关重要。这些数据 有可能减少日益增长的认知障碍负担，并影响大脑健康。 数以百万计的美国老年人。

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.