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

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.