Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer's disease (AD). Lipids are complex molecules comprising of many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 lipid species across 32 lipid (sub)classes) allows for detailed isomeric and isobaric lipid separation. We applied the methodology to examine plasma samples from the Australian Imaging, Biomarkers and Lifestyle flagship study of aging (AIBL, n = 1112) and serum from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 800) studies. Cross sectional analysis using both cohorts identified concordant unique peripheral signatures associated with AD. Specific pathways include; sphingolipids, including GM3 gangliosides, where their acyl composition drove the major associations, and lipids previously associated with dysfunctional lipid metabolism in cardiometabolic disease including the phosphatidylethanolamine and triglyceride classes. Infomation derived from improved isomeric seperation highlighted pathway-specific changes with ether lipids including plasmalogens implicating perixosmal dysfunction in disease pathology. Longitudinal analysis revealed similar lipid signitures in both AIBL and ADNI cohorts with future disease onset. We utilised the two independent studies to train and validate multivariate lipid models that significantly improved disease classification and prediction. Together our results provide a holistic view of the lipidome and its relationship with AD using a comprehensive lipidomics approach, providing targets for further mechanistic investigation.

中文翻译：

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结合两个大型临床队列（AIBL和ADNI）来识别流行性和偶发性阿尔茨海默氏病的多种脂质代谢途径。

脂质代谢的变化与阿尔茨海默氏病（AD）的发病和病理密切相关。脂质是由许多同分异构和同量异位物种组成的复杂分子，需要进行详细分析才能解释生物学意义。我们扩展的靶向脂质组学平台（涵盖32个脂质（亚）类的569种脂质）可实现详细的异构体和同量异位脂质分离。我们应用该方法检查了澳大利亚成像，生物标志物和生活方式衰老旗舰研究（AIBL，n = 1112）的血浆样本和阿尔茨海默氏病神经影像计划（ADNI，n = 800）研究的血清。使用这两个队列进行的横截面分析确定了与AD相关的一致的独特外周特征。具体途径包括：鞘脂，包括GM3神经节苷脂，其中的酰基组成是主要的关联因素，而以前与心脏代谢疾病中脂代谢异常有关的脂质包括磷脂酰乙醇胺和甘油三酸酯类。从改善的异构体分离中获得的信息突出显示了醚脂质的途径特异性变化，包括在疾病病理学中牵涉到perixosmal功能障碍的缩醛磷脂。纵向分析显示AIBL和ADNI队列中相似的脂质特征与未来疾病发作有关。我们利用两项独立研究来训练和验证可显着改善疾病分类和预测的多元脂质模型。通过综合的脂质组学方法，我们的结果共同提供了脂质组及其与AD关系的整体视图，