Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

Abbas Dehghan, Rui Climaco Pinto, Ibrahim Karaman, Jian Huang, Brenan R. Durainayagam, Mohsen Ghanbari, Areesha Nazeer, Qi Zhong, Sonia Liggi, Luke Whiley, Rima Mustafa, Miia Kivipelto, Alina Solomon, Tiia Ngandu, Takahisa Kanekiyo, Tomonori Aikawa, Carola I. Radulescu, Samuel J. Barnes, Gonçalo Graça, Elena ChekmenevaStephane Camuzeaux, Matthew R. Lewis, Manuja R. Kaluarachchi, M. Arfan Ikram, Elaine Holmes, Ioanna Tzoulaki, Paul M. Matthews, Julian L. Griffin, Paul Elliott

Research output: Contribution to journalArticlepeer-review


Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049–1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

Original languageEnglish (US)
Article numbere2206083119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number43
StatePublished - Oct 25 2022


  • ABCA7
  • Alzheimer’s disease
  • ceramide
  • genome-wide association study
  • metabolomics

ASJC Scopus subject areas

  • General


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