Blood Triglycerides and Fatty Acids in Alzheimer's: Genetics and Neuroimaging

项目总结/摘要 阿尔茨海默病（AD）构成了巨大的社会和个人负担。临床试验失败 表明需要更好地了解这种复杂疾病的机制。甘油三酯， 在常规临床检查中测量的脂肪酸是脂肪酸（FA）的来源。我们以前的工作表明， 多不饱和甘油三酯（PUTG）与AD之间存在显著相关性。有趣的是，这些推杆 被发现携带欧米伽-3多不饱和脂肪酸（n-3FAs）， 在老龄化人口中发挥作用。许多临床试验已经研究了AD患者中的n-3 FA补充， 但结果令人失望。文献确实表明，遗传因素对患者对 n-3 FA补充剂。APOE ε4是晚发性AD的遗传危险因素。在AD患者中， 非携带者的认知功能得到改善，而APOE ε4携带者的认知功能没有改善。 效益我们的目标是研究PUTG和n-3 FA与横截面和 AD生物标志物的纵向变化，以及PUTG和n-3 FA对病理性AD的基因组贡献。 AD机制。为了实现这一目标，我们将使用假设驱动的综合方法， 结合多组学（基因组学、代谢组学、转录组学）和多模式生物标志物（血液、CSF 神经成像）数据。我们将使用ADNI、WRAP和AMP-AD队列的数据。首先，我们展示初步的 基线n-3 FA与“A/T/N/V”（淀粉样蛋白、tau蛋白、神经变性和 微血管疾病负荷）生物标志物。我们将检验PUTG和基线时的n-3 FA是否预测 长达8年的A/T/N/V生物标志物的纵向变化和轻度认知功能障碍（MCI）的转换 从基线起36个月后AD。“A/T/N/V”是基于最近提出的NIA-阿尔茨海默氏症 使用CSF和神经影像学生物标志物（脑萎缩和白色）的协会2018研究框架 高密度体积（MRI）和脑葡萄糖代谢（FDG-PET））。第二，我们会调查 通过特别关注PUTG和n-3，可能有助于AD病理生理学的遗传机制 FA通路相关基因。利用公开的数据库，我们人工筛选了一个候选基因， 与PUTG和n-3 FA途径相关的列表，并发现血清PUTG水平与 候选基因我们将确定PUTG和n-3 FA相关通路的遗传变异是否与 基线时血清n-3 FA和A/T/N/V生物标志物，并预测A/T/N/V生物标志物的纵向变化。 最后，我们将确定这些候选基因是否在AD中差异表达，以及遗传变异是否 对血液和大脑中的基因表达水平有显著影响。我们的研究有很大的潜力， 提供了对PUTG和n-3 FA的血清水平如何与AD相关的深入了解，并产生了新的 基于基因验证机制的诊断和治疗靶点。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) constitutes a substantial societal and personal burden. Clinical trial failures indicate the need for a better mechanistic understanding of this complex disease. Triglycerides, which are measured in routine clinical check-ups, are a source of fatty acids (FAs). Our previous work has shown a significant association between polyunsaturated triglycerides (PUTGs) and AD. Interestingly, these PUTGs were found to carry omega-3 polyunsaturated fatty acids (n-3 FAs), which have shown to improve cognitive function in aging populations. Many clinical trials have investigated n-3 FA supplementation in AD patients, but have resulted in disappointment. The literature does suggest a genetic influence on patient response to n-3 FA supplementation. APOE ε4 is a genetic risk factor for late-onset AD. In AD patients, APOE ε4 noncarriers experience improved cognitive function, while APOE ε4 carriers do not experience the same benefit. Our goal is to investigate the association of PUTGs and n-3 FAs with cross-sectional and longitudinal changes in AD biomarkers, and the genomic contribution of PUTGs and n-3 FAs to pathologic AD mechanisms. To achieve this goal, we will use a hypothesis-driven, integrative approach that will incorporate multi-omics (genomics, metabolomics, transcriptomics) and multi-modal biomarker (blood, CSF, neuroimaging) data. We will use data from ADNI, WRAP, and AMP-AD cohorts. First, we show preliminary results for an association between baseline n-3 FAs and “A/T/N/V” (amyloid, tau, neurodegeneration, and microvascular disease burden) biomarkers at baseline. We will test if PUTGs and n-3 FAs at baseline predict longitudinal changes in A/T/N/V biomarkers up to 8 years and conversion of mild cognitive impairment (MCI) to AD after 36 months from baseline. “A/T/N/V” is based on the recently proposed NIA-Alzheimer’s Association 2018 Research Framework using CSF and neuroimaging biomarkers (brain atrophy and white matter hyperintensity volume (MRI) and brain glucose metabolism (FDG-PET)). Second, we will investigate genetic mechanisms that may contribute to AD pathophysiology by focusing specifically on PUTG and n-3 FA pathway-related genes. Using publicly available databases, we have manually curated a candidate gene list that is related to PUTG and n-3 FA pathways and found associations between serum PUTG levels and gene candidates. We will determine if genetic variation in PUTG and n-3 FA related-pathways associate with serum n-3 FAs and A/T/N/V biomarkers at baseline and predict longitudinal changes in A/T/N/V biomarkers. Finally, we will determine if these gene candidates are differentially expressed in AD and if genetic variations have significant effects on gene expression levels in blood and brain. Our study has strong potential to provide insight into how serum levels of PUTGs and n-3 FAs are associated with AD and to yield novel diagnostic and therapeutic targets based on genetic-validated mechanisms.