Abstract Background and Objective PSEN1 -H163Y carriers, at the presymptomatic stage, have reduced 18 FDG-PET binding in the cerebrum of the brain [1]. This could imply dysfunctional energy metabolism in the brain. In this study, plasma of presymptomatic PSEN1 mutation carriers was analyzed to understand associated metabolic changes. Methods We analyzed plasma from non-carriers (NC, n=8) and presymptomatic PSEN1 -H163Y mutation carriers (MC, n=6) via untargeted metabolomics using gas and liquid chromatography coupled with mass spectrometry, which identified 1199 metabolites. All the metabolites were compared between MC and NC using univariate analysis, as well as correlated with the ratio of Aβ 1-42/Aβ1-40 , using Spearman’s correlation. Altered metabolites were subjected to Ingenuity Pathways Analysis (IPA). Results When comparing between presymptomatic MC and NC, the levels of 116 different metabolites were altered. Out of 116, only 23 were annotated metabolites, which include amino acids, fatty acyls, bile acids, hexoses, purine nucleosides, carboxylic acids, and glycerophosphatidylcholine species. 1-docosapentaenoyl-GPC, glucose and uric acid were correlated with the ratio of plasma Aβ 1-42 /Aβ 1-40 (p &lt; 0.05). Conclusion This study finds dysregulated metabolite classes, which are changed before the disease onset. Also, it provides an opportunity to compare with sporadic Alzheimer’s Disease. Observed findings in this study need to be validated in a larger and independent Familial Alzheimer’s Disease (FAD) cohort. Graphical abstract

Plasma metabolomics of presymptomatic PSEN1-H163Y mutation carriers: A pilot study