Metabolic dysregulation in Alzheimer's disease: A brain metabolomics approach

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-09-11 DOI:10.1002/alz.70528

Anke Hüls, Youran Tan, Emma Casey, Zhenjiang Li, Marla Gearing, Allan I. Levey, James J. Lah, Aliza P. Wingo, Dean P. Jones, Douglas I. Walker, Thomas S. Wingo, Donghai Liang

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Abstract

INTRODUCTION

This study aimed to identify specific biological pathways and molecules involved in Alzheimer's disease (AD) neuropathology.

METHODS

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.

RESULTS

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.

DISCUSSION

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.

Highlights

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.

Abstract Image

查看原文本刊更多论文

阿尔茨海默病的代谢失调：脑代谢组学方法。

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。方法：我们对来自Emory阿尔茨海默病研究中心（ADRC）脑库的162个人类额叶皮层样本进行了尖端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。结果：我们确定了155个独特的代谢特征和36个与三种已建立的阿尔茨海默病神经病理标志物相关的途径。其中，18种新的代谢物被证实具有1级证据，表明它们参与了AD神经病理中的氨基酸代谢、脂质代谢、碳水化合物代谢、核苷酸代谢以及辅助因子和维生素的代谢。遗传变异影响了这些关联，载脂蛋白E (APOE) ε4等位基因的非携带者在代谢产物（包括葡萄糖和腺苷5′-二磷酸核糖）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病理分子机制方面的潜力。我们的研究结果为阿尔茨海默病的代谢失调及其与遗传因素的相互作用提供了重要的见解。这是人类脑组织中最大的非靶向代谢组学研究之一。155种代谢特征和36种代谢途径与阿尔茨海默病（AD）的神经病理学有关。其中，18种独特的代谢物被证实具有1级证据。葡萄糖和腺苷5'-二磷酸核糖被确定为AD的关键代谢改变。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.