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积累中。 脂质组学正在为AD患者脂代谢改变及其在脑中的作用提供新的见解 衰老。由MPI Kaddurah-Daouk领导的AD代谢组学联盟(ADMC)是加速 药物伙伴关系-AD(AMP-AD)，在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 跨不同队列的高质量代谢组学/脂质组学数据集的代谢组具有快速和广泛的 数据共享和透明的方法报告，以最大限度地提高严密性和可重复性。我们定义了新陈代谢 跨越疾病轨迹的故障，连接外周和中枢变化，描绘基因 调节AD努力中的代谢变化，导致药物开发的新靶点。MPI阿诺德领衔 用于AD及其生物标志物研究的数据集成资源--首个AD分子图谱的构建 在一个多组学的背景下。世界著名的脂质组学专家MPI Meikle已经创造了超过5万种血浆 来自里程碑式研究的脂肪组谱，包括AD队列(ADNI、AIBL、NSHDS)和最先进的 来自ROS/MAP队列的人脑样本的脂肪组学分析。我们最新的工作，掺入脂肪组学 在AD队列中进行脂肪组学分析，并发现与载脂蛋白E风险相关的外周乙醚类脂类 和韧性变种。脂类代谢随年龄变化，潜在地调节年龄的影响，年龄是最强的 AD上负荷的风险系数。然而，目前尚不清楚年龄和脂肪代谢如何相互作用来影响衰老。 脑和阿尔茨海默病易感性。对这些关系的更好理解将为以下方面打开新的机会 修改调节免疫系统和保护大脑的脂代谢途径的早期干预 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。目标1 获得代谢弹性和易感性的可重复的外周和中央脂肪体学特征 认知能力下降并计算代谢风险分数(MRS)，以告知AD风险和大脑老化。目标2 将AD风险基因与脆弱性和恢复力相关的脂类调节效应编目。建立在我们的 方法用GWA法、中介分析法和 孟德尔随机化分析揭示与阿尔茨海默病和高血压相关的遗传调节血脂改变 大脑老化。目标3：评估生活方式干预对我们衍生的脂组特征的影响，以确定 这些干预措施可以改善血脂失调，以维持大脑健康和防止认知能力下降。 探索性目标：对外周(免疫)细胞进行脂肪组学分析，以捕获细胞脂体并与之相关 这与脑老化和AD的发病机制有关。我们的研究结果将提供对角色的更深层次的理解 在脑老化和阿尔茨海默病中的脂类药物，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.