Understanding mechanisms and seeking novel biomarkers in Alzheimer's disease

1.我们扩展了我们的研究，测试阿尔茨海默病(AD)的代谢紊乱，以确定大脑葡萄糖利用、磷脂/脂肪酸代谢、胆固醇/氧固醇生物合成以及多胺代谢和转甲基化反应的明显异常。 2.我们已经启动了对真实世界处方数据集的分析，以验证针对代谢异常的药物可能改变AD发病风险的假设。我们的假设是，接触这些药物中的一种或多种可以预防AD。这将为在随机临床试验(RCT)中进一步证实提供强有力的理由。我们已经通过AD专项基金获得了NIA IRP的支持，以用于“药物再用途用于有效的阿尔茨海默氏症药物(DREAM)”研究。它与国家阿尔茨海默病项目法案(NPA)中的里程碑之一非常一致，即启动翻译生物信息学和网络药理学的研究计划，以支持合理的药物重新定位和从发现到临床开发的联合治疗。 3.虽然肥胖、糖尿病和高胆固醇血症等心血管危险因素会增加AD的风险，但代谢综合征(METS)的生物学机制尚不清楚。这些风险因素是否通过来自不同环境、文化和遗传背景的老年人的共同机制发挥作用，也是未知的。为了解决这个问题，我们比较了巴尔的摩老龄化纵向研究(BLSA)和Tsuruoka代谢组学队列研究(TMCS)的老年人血清代谢物谱与METS的相关性。我们的结果表明，在北美和日本的老年人中，存在与甲硫氨酸相关的共同和独特的血液代谢物特征。这些研究为开发针对阿尔茨海默病等疾病代谢异常的个性化治疗提供了希望。

1. We have expanded on our studies testing metabolic perturbations in Alzheimer's disease (AD) to identify distinct abnormalities in brain glucose utilization, phospholipid/fatty acid metabolism, cholesterol/oxysterol biosynthesis as well as polyamine metabolism and transmethylation reactions. 2. We have initiated analyses of real-world prescription datasets to test the hypothesis that drugs targeting abnormal metabolism may alter the risk of incident AD. Our hypothesis is that exposure to one or more of these drugs will protect against AD. This will provide a strong rationale for further confirmation in randomized clinical trials (RCTs). We have secured support from the NIA IRP through special-AD funds for the 'Drug Repurposing for Effective Alzheimers Medicines (DREAM)' study. It aligns well with one of the milestones in the National Alzheimer's Project Act (NAPA) i.e. Initiate research programs for translational bioinformatics and network pharmacology to support rational drug repositioning and combination therapy from discovery through clinical development. 3. While cardiovascular risk factors such as obesity, diabetes and hypercholesterolemia increase the risk of AD, the biological mechanisms underlying metabolic syndrome (MetS) are unclear. Whether these risk factors operate through shared mechanisms in older individuals from diverse environmental, cultural and genetic backgrounds, is also unknown. We have compared associations between serum metabolite profiles and MetS in older individuals from the Baltimore Longitudinal Study of Aging (BLSA) and the Tsuruoka Metabolomics Cohort Study (TMCS) to address this question. Our results suggest that there are both shared and unique blood metabolite signatures associated with MetS in North American and Japanese older individuals. These studies hold promise for the development of personalized treatments targeting abnormal metabolism in diseases such as AD.