Genome-wide association studies (GWAS) have identified genetic loci associated with risk of Alzheimer’ s disease (AD), but underlying mechanisms are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWAS using untargeted metabolic profiling (metabolomics) by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer)s with AD-related single nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0x 10−5 to 1.3 × 10−44). We show that plasma LacCer concentrations are associated with cognitive performance in humans and, in brain tissue from ABCA7-null mice, we found differing concentrations of sphingomyelins, ceramides, and hexose-ceramides compared to wild type (WT) (P =0.049 to 1.4 x10−5). We then used Mendelian randomisation to show that the association of LacCer with AD risk is potentially causal. Our work suggests that AD risks arising from functional variations in ABCA7 are mediated at least in part through ceramides; alterations in their metabolism or downstream signalling may offer new therapeutic opportunities in AD.

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Metabolome-wide association study on ABCA7 demonstrates a role for ceramide metabolism in impaired cognitive performance and Alzheimer’s disease

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Metabolome-wide association study on ABCA7 demonstrates a role for ceramide metabolism in impaired cognitive performance and Alzheimer’s disease