GENOMICS AND IMAGING DATA INFORMED METABOLOMICS: A BIOCHEMICAL ROADMAP FOR ALZHEIMER DISEASE

Abstract

Increasing evidence supports that Alzheimer disease (AD) is a metabolic disease with high diabetes co-morbidity and a wide range of metabolic perturbations occurring early in the disease process. While genetic risk clearly plays a role in AD, the gut microbiome, exposome and diet also exert influences on brain metabolic health. Advances in analytical chemistry enable simultaneous measurement of 1000's of metabolites that can be integrated into tissue-specific metabolic networks enabling a new kind of metabolic systems analysis of AD and where peripheral and central metabolic changes can be connected. We will highlight developments in the metabolomics field and large initiatives within Accelerated Medicine Partnership (AMP-AD) and MOVE AD where metabolomics data is being generated and informed by genomics and imaging data. Fasting baseline serum samples from Alzheimer's Disease Neuroimaging Initiative ADNI1 (199 CN, 356 LMCI and 175 AD participants) were analyzed using targeted (AbsoluteIDQ-p180 and Biocrates Bile Acid Kit) and non-targeted metabolomics and lipidomics platforms (UPLC-TOF MS; UPLC-QTOF MS). ADNI GO/2 (150 CN, 100 SMC, 100 EMCI, 150 LMCI, and 150 mild AD) and Rotterdam studies were used for validation of findings. Partial correlation networks revealed changes in sphingomyelins and ether-containing phosphatidylcholines in preclinical biomarker-defined AD stages providing mechanistic insights about abeta and tau pathology and pointing to changes in membrane structure and function. Subsequent changes in acylcarnitines and several amines, including the branched chain amino acid valine and α-aminoadipic acid correlated with imaging changes and cognitive decline pointing to a role of mitochondrial energetics. Several metabolic changes related to liver enzymatic functions and gut microbiome activity correlated with imaging and cognitive changes highlighting a possible role for gut liver brain axis in disease pathogenesis. Meta-analysis across metabolomics studies reveals common biochemical findings when evaluated within a metabolic network context. Metabolomics identified key disease-related metabolic changes and disease-progression-related changes some related to liver and gut microbiome activity. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. Genomics and imaging data inform metabolomics data and together they provide a powerful systems approach for the study of AD.