Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer disease brains

The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence to support that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain, including information on treatment targets. In this study, we interrogate the metabolomic and lipidomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE {varepsilon}4 and TREM2 risk variant carriers, and non-carrier sporadic AD (sAD). We generated metabolomic and lipidomic data from parietal cortical tissue from 366 participants with AD pathology and 26 cognitively unimpaired controls using the Metabolon global metabolomics platform. We identified 133 metabolites associated with disease status (FDR q-value<0.05). In sAD brains these include tryptophan betaine (b=-0.57) and N-acetylputrescine (b=-0.14). Metabolites associated with sAD and ADAD include ergothioneine (b=-0.21 and -0.26 respectively) and serotonin (b=-0.34 and -0.58, respectively). TREM2 and ADAD showed association with -tocopherol (b=-0.12 and -0.12) and CDP-ethanolamine (b=-0.13 and -0.10). {beta}-citrylglutamate levels are associated with sAD, ADAD, and TREM2 compared to controls (b=-0.15; -0.22; and -0.29, respectively). Additionally, we identified a signature of 16 metabolites that is significantly altered between genetic groups (sAD vs. control p = 1.05x10-7, ADAD vs. sAD p = 3.21x10-5) and is associated with Braak tau stage and disease duration. These data are available to the scientific community through a public web browser (http://ngi.pub/Metabolomics). Our findings were replicated in an independent cohort of 327 individuals.