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

Genome-wide association studies (GWAS) have identified genetic loci associated with risk of Alzheimer's disease (AD), but underlying mechanisms are largely unknown. Using untargeted mass spectrometry, we conducted a metabolome-wide association study (MWAS) that identified the association of lactosylceramides (LacCer)s with AD-related single nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0x 10-5 to 1.3 x 10-44). Independent support for the association came through the discovery of differences in concentrations of sphingomyelins, ceramides, and hexose-ceramides in brain tissue from ABCA7-null mice compared to wild type (P =0.049 -1.44 x10-5). We showed that plasma LacCer concentrations are associated with cognitive performance in humans. We found evidence for a potentially causal association of LacCer with AD risk using Mendelian randomisation analysis. Our work suggests that AD risks arising from functional variations in ABCA7 expression are mediated at least in part through ceramides, the metabolism or downstream signalling of which offers new therapeutic opportunities.