Mares Jason, Costa Ana Paula, Dartora William J, Wartchow Krista M, Lazarian Artur, Bennett David A, Nuriel Tal, Menon Vilas, McIntire Laura Beth J
Center for Translational & Computational Neuroimmunology, Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, United States.
Lipidomics and Biomarker Discovery Lab, Department of Radiology, Brain Health Imaging Institute, Weill Cornell Medicine, New York, NY, United States.
Front Aging Neurosci. 2024 Jun 11;16:1419253. doi: 10.3389/fnagi.2024.1419253. eCollection 2024.
At least one-third of the identified risk alleles from Genome-Wide Association Studies (GWAS) of Alzheimer's disease (AD) are involved in lipid metabolism, lipid transport, or direct lipid binding. In fact, a common genetic variant (ε4) in a cholesterol and phospholipid transporter, Apolipoprotein E (), is the primary genetic risk factor for late-onset AD. In addition to genetic variants, lipidomic studies have reported severe metabolic dysregulation in human autopsy brain tissue, cerebrospinal fluid, blood, and multiple mouse models of AD.
We aimed to identify an overarching metabolic pathway in lipid metabolism by integrating analyses of lipidomics and transcriptomics from the Religious Order Study and Rush Memory Aging Project (ROSMAP) using differential analysis and network correlation analysis.
Coordinated differences in lipids were found to be dysregulated in association with both mild cognitive impairment (MCI) and carriers. Interestingly, these correlations were weakened when adjusting for education. Indeed, the cognitively non-impaired carriers have higher education levels in the ROSMAP cohort, suggesting that this lipid signature may be associated with a resilience phenotype. Network correlation analysis identified multiple differential lipids within a single module that are substrates and products in the Lands Cycle for acyl chain remodeling. In addition, our analyses identified multiple genes in the Lands Cycle acyl chain remodeling pathway, which were associated with cognitive decline independent of amyloid-β (Aβ) load and tau tangle pathologies.
Our studies highlight the critical differences in acyl chain remodeling in brain tissue from carriers and individual non-carriers with MCI. A coordinated lipid profile shift in dorsolateral prefrontal cortex from both carriers and MCI suggests differences in lipid metabolism occur early in disease stage and highlights lipid homeostasis as a tractable target for early disease modifying intervention.
在阿尔茨海默病（AD）全基因组关联研究（GWAS）中确定的风险等位基因中，至少三分之一参与脂质代谢、脂质转运或直接脂质结合。事实上，胆固醇和磷脂转运蛋白载脂蛋白E（ApoE）中的一种常见基因变异（ε4）是晚发性AD的主要遗传风险因素。除了基因变异外，脂质组学研究报告称，在人类尸检脑组织、脑脊液、血液以及AD的多个小鼠模型中存在严重的代谢失调。
我们旨在通过对宗教团体研究和拉什记忆与衰老项目（ROSMAP）的脂质组学和转录组学进行整合分析，利用差异分析和网络相关性分析，确定脂质代谢中的一个总体代谢途径。
发现脂质的协调差异与轻度认知障碍（MCI）和ApoE携带者均失调相关。有趣的是，在调整教育因素后，这些相关性减弱。事实上，在ROSMAP队列中，认知未受损的ApoE携带者具有更高的教育水平，这表明这种脂质特征可能与一种复原力表型相关。网络相关性分析在单个模块中确定了多种差异脂质，它们是Lands循环中酰基链重塑的底物和产物。此外，我们的分析确定了Lands循环酰基链重塑途径中的多个基因，这些基因与认知衰退相关，独立于淀粉样β蛋白（Aβ）负荷和tau缠结病理。
我们的研究突出了ApoE携带者和患有MCI的非携带者个体脑组织中酰基链重塑的关键差异。来自ApoE携带者和MCI患者的背外侧前额叶皮质中脂质谱的协调变化表明，脂质代谢差异在疾病早期就已出现，并突出了脂质稳态作为早期疾病修饰干预的一个可处理靶点。
