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

Dehghan, A.; Pinto, R.; Karaman, I.; Hung, J.; Durainayagam, B.; Liggi, S.; Whiley, L.; Mustafa, R.; Kivipelto, M.; Solomon, A.; Ngandu, T.; Takahisa, K.; Tomonori, A.; Chekmeneva, E.; Camuzeaux, S.; Lewis, M. R.; Kaluarachi, M.; Ghanbari, M.; Ikram, M. A.; Holmes, E.; Tzoulaki, I.; Matthews, P.; Griffin, J.; Elliott, P.

2021-04-29 neurology
10.1101/2021.04.06.21254991 medRxiv
Show abstract

Genome-wide association studies (GWAS) have identified genetic loci associated with risk of Alzheimers 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) with AD-related single nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0x 10-5 to 1.3 x 10-44). We show that plasma LacCer concentrations are associated with cognitive performance in humans and concentrations of sphingomyelins, ceramides, and hexose-ceramides were altered in brain tissue from ABCA7 knock out mice, 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 risk for AD arising from functional variations in ABCA7 are mediated at least in part through ceramides. Modulation of their metabolism or downstream signalling may offer new therapeutic opportunities for AD.

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