Human gray and white matter metabolomics to differentiate APOE-dependent metabolic changes in early and late Alzheimer's disease.

Abstract

Many have suggested that irregularities in metabolism play an underlying role in the progression of Alzheimer's Disease (AD). A detailed knowledge of the biochemical composition of AD brain tissue vs normal brain tissue will be key in understanding the metabolic processes underlying AD, especially as they relate to APOE genotype. Here we perform a metabolomics analysis on the brain tissue of a large cohort of community-based participants in the UK-ADC brain bank to characterize the biochemical profiles of brains with and without Alzheimer's disease and other mixed pathologies based on APOE genotype and disease stage. The global biochemical profiles of post-mortem human brain tissue from the gray matter of Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 158 community-based older adult volunteers was analyzed. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch's two-sample t-test to approximate fold change of metabolites between disease stage and APOE genotype. Random forest was used to rank metabolites in order of importance for predicting AD presence in tissue. Late stage disease in the APOE E4 genotype has decreases in lysophospholipids, long chain polyunsaturated fatty acids, endocannabinoids, and branched fatty acids as well as N-acetylserine in the gray matter. Late stage disease in the APOE E4 genotype has increases in phospholipid metabolism and decreases in amino acid metabolism and Vitamin B6. The APOE E4 genotype is associated with increases in gamma-glutamyl amino acids, lysophospholipid, and amino acid metabolism and decreases in urea cycle, sterol, stachydrine, and benzoate metabolism during early stages of disease, but that there are few metabolic differences between genotypes in later disease. Alzheimer's disease has increases in phospholipid metabolism and decreases in amino acid metabolism compared to normal. Early stage disease showed many metabolic differences between genotypes and late stage tissues looked remarkably similar across genotype. This suggests there may be metabolically distinct pathways that each genotype takes to produce a tissue with common endpoint of disease characterized by an AD biochemical profile. Further studies are needed to examine whether these metabolites are consistently altered in Alzheimer's disease.