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

脂质在脑老化和阿尔茨海默病（AD）及其相关痴呆（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脑中的作用相关的新见解 衰老由MPI Kaddurah-Daouk领导的AD代谢组学联盟（ADMC）是加速 药品合作伙伴-AD（AMP-AD）与AD研究，代谢组学/脂质组学， 信息学、机器学习和建模。在过去的八年里，我们投入了大量的精力来探索AD 代谢组学与高质量的代谢组学/脂质组学数据集跨不同的队列，快速和广泛的 数据共享和透明的方法报告，以最大限度地提高严谨性和可重复性。我们定义代谢 在整个疾病的轨迹失败，连接外围和中央的变化，描绘遗传 调节AD中的代谢变化，从而为药物开发提供新的靶点。MPI阿诺德领导了 构建首个AD分子图谱，为AD及其生物标志物研究提供数据整合资源 in a multi-multi-omics多组学context上下文. MPI Meikle是世界知名的脂质组学专家， 里程碑研究的脂质组学特征，包括AD队列（ADNI、Aibl、NSHDS）和最先进的 来自ROS/MAP组群的人脑样品的脂质组学分析。我们最近的工作，包括脂质组学 在AD队列中使用脂质组学分析的GWAS，并确定与ApoE风险相关的外周醚脂质 和弹性变体。脂质代谢随年龄变化，可能介导年龄的影响，最强的 AD上LOAD的风险系数。然而，年龄和脂质代谢如何相互作用影响衰老尚不清楚 大脑和AD易感性。对这些关系的更好理解将为以下方面提供新的机会： 早期干预以改变调节免疫系统和保护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性目标。要求1 获得可重复的外周和中枢脂质组学特征，用于代谢弹性和对 认知下降和计算代谢风险评分（MRS），告知AD风险和大脑老化。目的2 将AD风险基因型的脂质介导效应与脆弱性和恢复力联系起来。充分发挥两国 方法来表征与APOE等位基因相关的脂质体，我们将使用GWAS，中介分析和 孟德尔随机化分析旨在揭示与AD有因果关系的遗传调节脂质变化， 大脑老化目的3：评估生活方式干预对我们衍生的脂质组学特征的影响，以确定 这些干预措施可以改善脂质失调，以维持大脑健康和预防认知能力下降。 探索性目的：对外周（免疫）细胞进行脂质组学分析，以捕获细胞脂质组并将其与 这与脑老化和AD发病机制有关。我们的研究结果将提供更深入的了解， 脂质在脑老化和AD中的作用，并将导致新的治疗方法。

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.