Hüls Anke, Tan Youran, Casey Emma, Li Zhenjiang, Gearing Marla, Levey Allan I, Lah James J, Wingo Aliza P, Jones Dean P, Walker Douglas I, Wingo Thomas S, Liang Donghai
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
Alzheimers Dement. 2025 Sep;21(9):e70528. doi: 10.1002/alz.70528.
This study aimed to identify specific biological pathways and molecules involved in Alzheimer's disease (AD) neuropathology.
We conducted cutting-edge high-resolution metabolomics profiling of 162 human frontal cortex samples from the Emory Alzheimer's Disease Research Center (ADRC) brain bank with comprehensive neuropathological evaluations.
We identified 155 unique metabolic features and 36 pathways associated with three well-established AD neuropathology markers. Of these, 18 novel metabolites were confirmed with level 1 evidence, implicating their involvement in amino acid metabolism, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and metabolism of cofactors and vitamins in AD neuropathology. Genetic variability influenced these associations, with non-carriers of the apolipoprotein E (APOE) ε4 allele showing stronger perturbations in metabolites including glucose and adenosine 5'-diphosphoribose.
This study demonstrates the potential of high-resolution metabolomic profiling in brain tissues to elucidate molecular mechanisms underlying AD pathology. Our findings provide critical insights into metabolic dysregulation in AD and its interplay with genetic factors.
This is one of the largest untargeted metabolomics studies of human brain tissue. 155 metabolic features, and 36 metabolic pathways were linked to Alzheimer's disease (AD) neuropathology. Of these, 18 unique metabolites were confirmed with level 1 evidence. Glucose and adenosine 5'-diphosphoribose identified as key metabolic alterations in AD.
本研究旨在确定参与阿尔茨海默病（AD）神经病理学的特定生物学途径和分子。
我们对来自埃默里阿尔茨海默病研究中心（ADRC）脑库的162份人类额叶皮质样本进行了前沿的高分辨率代谢组学分析，并进行了全面的神经病理学评估。
我们确定了155种独特的代谢特征和36条与三种已确立的AD神经病理学标志物相关的途径。其中，18种新代谢物得到了一级证据的证实，表明它们参与了AD神经病理学中的氨基酸代谢、脂质代谢、碳水化合物代谢、核苷酸代谢以及辅因子和维生素代谢。基因变异性影响了这些关联，载脂蛋白E（APOE）ε4等位基因的非携带者在包括葡萄糖和5'-二磷酸腺苷核糖在内的代谢物中表现出更强的扰动。
本研究证明了脑组织中高分辨率代谢组学分析在阐明AD病理学潜在分子机制方面的潜力。我们的发现为AD中的代谢失调及其与遗传因素的相互作用提供了关键见解。
这是对人类脑组织进行的最大规模的非靶向代谢组学研究之一。155种代谢特征和36条代谢途径与阿尔茨海默病（AD）神经病理学相关。其中，18种独特的代谢物得到了一级证据的证实。葡萄糖和5'-二磷酸腺苷核糖被确定为AD中的关键代谢改变。
