The landscape of metabolic brain alterations in Alzheimer’s disease

Abstract

AbstractWe present a comprehensive reference map of metabolic brain changes in Alzheimer’s disease (AD). In a multi-center study within the Accelerating Medicines Partnership in AD, we metabolically profiled 500 samples from the dorsolateral prefrontal cortex (DLPFC) and 83 samples from the temporal cortex (TCX). In the DLPFC, 298 metabolites were correlated with AD-related traits, including late-life cognitive performance and neuropathological β-amyloid and tau tangle burden. Out of these 298 metabolites, 35 replicated in TCX and a previous study. A conditional analysis suggests that metabolic associations with tangle burden were largely independent of β-amyloid load in the brain. Our results provide evidence of brain alterations in bioenergetic pathways, cholesterol metabolism, neuroinflammation, osmoregulation, and other pathways. In a detailed investigation of the glutamate/GABA neurotransmitter pathway, we demonstrate how integration of complementary omics data can provide a comprehensive view of dysregulated biochemical processes. All associations are available as an interactive network at https://omicscience.org/apps/brainmwas/.