Untargeted Metabolomics Shows Alterations in Homocysteine, Lipids, and Fatty Acids Predicting Memory Decline in Healthy Middle-Aged Individuals

INTRODUCTION: Some aspects of memory start declining in the fifth decade which may be related to systemic metabolic changes. These changes have not been fully identified. This is the first Metabolome-Wide Association Study of the human plasma for the longitudinal change in memory in healthy adults. METHODS: Ultra-high resolution mass spectrometry with liquid chromatography was performed on 207 University employees9 plasma. RESULTS: From 10,201 measured metabolic features, 558 differed between those experiencing change vs no change in memory (False Discovery Rate, FDR< 0.2). Differentially abundant metabolites were observed in lipid and fatty acid metabolism pathways: glycerophospholipid (p=0.0003), fatty acid (p=0.0003) and linoleate (p=0.0003) pathways. Within these pathways, higher homocysteine (OR for memory decline=1.09, FDR=0.19) and lower arachidonic acid (OR=0.97, FDR=0.19), sterol (OR=0.92, FDR=0.02), acetylcholine (OR=0.78, FDR=0.19), carnitine (OR=0.75, FDR=0.19) and linoleic acid (OR=0.74, FDR=0.19) were associated memory decline. DISCUSSION: Altered systemic lipid and fatty acid are linked with early memory decline in middle-aged individuals. Keywords: memory decline, metabolomics, fatty acid metabolism, mass spectrometry, liquid chromatography