Metabolic age to define influences of the lipidome on brain aging in Alzheimer's disease

代谢年龄确定脂质组对阿尔茨海默氏病大脑衰老的影响

• 批准号: 10643738
• 负责人: Matthias Arnold
• 金额: $ 72.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643738
• 关键词: Acceleration; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Apolipoprotein E; Area; Atlases; Biochemical Pathway; Biochemistry; Biological Markers; Brain; Brain imaging; CD36 gene; Catalogs; Cells; Cognition; Data; Data Set; Dementia; Diet; Disease; Disease Progression; Disease susceptibility; Drug Targeting; Early Intervention; Early identification; Ethers; Evolution; Failure; Genes; Genetic; Genotype; Glucose; Heterogeneity; Human; Immune; Immune system; Impaired cognition; Informatics; Intervention; Investments; Late Onset Alzheimer Disease; Least-Squares Analysis; Life Style; Link; Lipids; Machine Learning; Maps; Mediating; Mediation; Medicine; Mendelian randomization; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Monitor; Nerve Degeneration; Outcome; Pathogenesis; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Population Study; Predisposition; Prevention; Process; Regulation; Reporting; Reproducibility; Research; Resources; Risk; Risk Factors; Role; Sampling; Sex Differences; Systemic disease; Time; Treatment Efficacy; Variant; Work; age effect; aging brain; amyloid pathology; biobank; blood lipid; brain health; cognitive change; cohort; data integration; data sharing; drug development; drug discovery; genetic risk factor; genome wide association study; high risk; immune function; immunoregulation; improved; insight; lifestyle intervention; lipid metabolism; lipid transport; lipidome; lipidomics; loss of function; metabolome; metabolomics; multiple omics; new therapeutic target; novel; novel therapeutic intervention; predictive signature; preservation; prevent; resilience; risk variant; tool

Evidence for the roles of lipids in brain aging and Alzheimer (AD) and its related dementias (ADRD) is building. Lipidomics is providing new insights related to altered lipid turnover and metabolism in AD and their roles in brain aging. Our AD Metabolomics Consortium (ADMC) led by MPI Kaddurah-Daouk is part of the Accelerating Medicines Partnership-AD (AMP-AD) with centers of excellence in AD research, metabolomics/lipidomics, informatics, machine learning, and modeling. Over the last eight years we invested major effort exploring the AD metabolome with high-quality metabolomics/lipidomics datasets across different cohorts with rapid and broad data sharing and transparent reporting of methods, to maximize rigor and reproducibility. We defined metabolic failures across the trajectory of disease, connecting peripheral and central changes, delineating genetic modulation of metabolic changes in AD effort that lead to novel targets for drug development. MPI Arnold led the construction of the first molecular atlas for AD, a data integration resource for investigating AD and its biomarkers in a multi-omics context. MPI Meikle, a world-renowned expert in lipidomics, has created over 50,000 plasma lipidomic profiles from landmark studies, including AD cohorts (ADNI, AIBL, NSHDS) and the most advanced lipidomic profiling of human brain samples from the ROS/MAP cohorts. Our recent work, incorporated lipidomic GWAS with lipidomic profiling in AD cohorts and identified peripheral ether lipids associated with the ApoE risk and resilience variants. Lipid metabolism changes with age, potentially mediating the effects of age, the strongest risk factor for LOAD, on AD. However, it is unclear how age and lipid metabolism interact to affect the aging brain and AD susceptibility. An improved understanding of these relationships will open up new opportunities for early interventions to modify lipid metabolism pathways that modulate the immune system and preserve brain health. We will use state-of-the-art lipidomics to enable three complementary and one exploratory aim. Aim 1 derive reproducible peripheral and central lipidomic signatures for metabolic resilience and vulnerability to cognitive decline and calculate metabolic risk scores (MRS) that inform on AD risk and brain aging. Aim 2 catalogue the lipid-mediated effects of AD risk genotypes linked to vulnerability and resilience. Building on our methods to characterize the lipidome associated with APOE alleles, we will use GWAS, mediation analysis and Mendelian randomization analyses to uncover genetically modulated lipid alterations causally linked to AD and brain aging. Aim 3: evaluate the effects of lifestyle interventions on our derived lipidomic signatures to identify those interventions that can ameliorate lipid dysregulation to sustain brain health and prevent cognitive decline. Exploratory aim: perform lipidomic profiling of peripheral (immune) cells to capture a cellular lipidome and relate this to brain aging and AD pathogenesis. The outcome of our research will provide deeper understanding of role of lipids in brain aging and in AD and will lead to novel therapeutic approaches.

脂质在大脑衰老和阿尔茨海默氏症（AD）及其相关痴呆症（ADRD）中的作用的证据正在建立。 脂质组学提供了与AD中脂质周转和代谢改变及其在大脑中的作用有关的新见解 老化。我们由MPI Kaddurah-Daouk领导的AD代谢组学联盟（ADMC）是加速的一部分 药物合作伙伴关系（AMP-AD），具有广告研究，代谢组学/脂质组学的卓越中心， 信息学，机器学习和建模。在过去的八年中，我们投入了大量努力来探索广告 具有高质量代谢组学/脂肪组学数据集的代谢组，跨不同的同类群 数据共享和方法的透明报告，以最大程度地提高严格和可重复性。我们定义了代谢 整个疾病轨迹的失败，连接外围和中心变化，描述遗传 代谢变化的AD努力的调节导致了药物开发的新目标。 MPI Arnold领导 构建用于AD的第一个分子地图集，这是用于研究AD及其生物标志物的数据集成资源 在多摩斯环境中。 MPI Meikle是一位世界知名的脂肪组学专家，创造了50,000多个等离子体 具有里程碑意义研究的脂质组学概况，包括广告群（ADNI，AIBL，NSHDS）和最先进的 来自ROS/MAP队列的人脑样品的脂质组分析。我们最近的工作，融合了脂肪组学 GWA具有脂肪组分析的GWA在AD队列中，并确定了与ApoE风险相关的周围醚脂质 和弹性变体。脂质代谢随着年龄的增长而变化，可能介导年龄的影响，最强 负载的风险因素，AD。但是，尚不清楚年龄和脂质代谢如何相互作用以影响衰老 大脑和广告敏感性。对这些关系的改进理解将为 早期干预措施修改调节免疫系统并保存大脑的脂质代谢途径 健康。我们将使用最先进的脂质组学来实现三个互补和一个探索目标。目标1 得出代谢弹性和脆弱性的可重现外围和中央脂质组学特征 认知能力下降和计算代谢风险评分（MRS），这些风险和大脑衰老的信息。目标2 分类与脆弱性和弹性有关的AD风险基因型的脂质介导的影响。建立在我们的基础上 表征与ApoE等位基因相关的脂质组的方法，我们将使用GWAS，调解分析和 Mendelian随机分析，以发现与AD的因果关系的遗传调节脂质改变和 脑老化。目标3：评估生活方式干预对我们衍生的脂肪组学特征的影响 那些可以改善脂质失调以维持大脑健康并预防认知能力下降的干预措施。 探索性目的：对周围（免疫）细胞的脂质组分析捕获细胞脂质组并相关 这是大脑衰老和AD发病机理的。我们研究的结果将为角色提供更深入的了解 大脑衰老和AD中的脂质的脂质，并将导致新颖的治疗方法。