Dataset Information

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

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.

SUBMITTER: Huls A

PROVIDER: S-EPMC12423944 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Hüls Anke A Tan Youran Y Casey Emma E Li Zhenjiang Z Gearing Marla M Levey Allan I AI Lah James J JJ Wingo Aliza P AP Jones Dean P DP Walker Douglas I DI Wingo Thomas S TS Liang Donghai D

Alzheimer's & dementia : the journal of the Alzheimer's Association 20250901 9

<h4>Introduction</h4>This study aimed to identify specific biological pathways and molecules involved in Alzheimer's disease (AD) neuropathology.<h4>Methods</h4>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.<h4>Results</h4>We identified 155 unique metabolic features and 36 pathways associated with three well-established AD ne ...[more]

PMID: 40931996

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Project description:Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.

Dataset Information

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

Introduction

Methods

Results

Discussion

Highlights

Publications

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

Similar Datasets

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