Lipidomic signatures for APOE genotypes provides new insights about mechanisms of resilience in Alzheimer’s disease

Tingting Wang, Kevin Huynh, Corey Giles, Wei Ling Florence Lim, Thy Duong, Natalie A. Mellett, Alexander Smith, Gavriel Olshansky, Brian G. Drew, Gemma Cadby, Phillip E. Melton, Joseph Hung, John Beilby, Gerald F. Watts, Pratishtha Chatterjee, Ian Martins, Simon M. Laws, Ashley I. Bush, Christopher C. Rowe, Victor L. VillemagneDavid Ames, Colin L. Masters, Matthias Arnold, Gabi Kastenmüller, Kwangsik Nho, Andrew J. Saykin, Rebecca Baillie, Xianlin Han, Ralph N. Martins, Eric Moses, Rima F. Kaddurah‐Daouk, Peter J Meikle

Research output: Contribution to journalConference articlepeer-review


The apolipoprotein E gene (APOE) genotype is the first and strongest genetic risk factor for late-onset Alzheimer’s disease and has emerged as a novel therapeutic target for AD. The encoded protein (Apolipoprotein E, APOE) is well-known to be involved in lipoprotein transport and metabolism, but its effect on lipid metabolic pathways and the potential mediating effect of these on disease risk have not been fully defined.

We performed lipidomic analysis on three independent cohorts (AIBL, n = 693; ADNI, n=207; BHS, n=4,384) and defined the association between APOE polymorphisms (ε4 and ε2) and plasma lipid species. To identify associations independent of lipoprotein metabolism, the analyses was performed with adjustment for clinical lipids (total cholesterol, HDL-C and triglycerides). Causal mediation analysis was performed to estimate the proportion of risk in the outcome model explained by a direct effect of APOE genotype on prevalent AD — the average direct effect (ADE) — and the proportion that was mediated by lipid species or lipidomic risk models — the average causal mediation effect (ACME).

We identified multiple associations of species from lipid classes such as ceramide, hexosylceramide, sphingomyelin, plasmalogens, alkyldiacylglycerol and cholesteryl esters with APOE polymorphisms (ε4 and ε2) that were independent of clinical lipoprotein measurements. There were 104 and 237 lipid species associated with APOE ε4 and ε2 respectively which were largely discordant. Of these 116 were also associated with Alzheimer’s disease. Individual lipid species (notably the alkyldiacylglycerol subspecies) or lipidomic risk models of APOE genotypes mediated up to 10% and 30% of APOE ε4 and ε2 treatment effect on AD risks respectively.

We demonstrate a strong relationship between APOE polymorphisms and peripheral lipid species. Lipids species mediate a proportion of the effects of APOE genotypes in risk of AD, particularly resilience with e2. Our results highlight the involvement of lipids in how APOE e2 mediates its resilience to AD and solidify their involvement with the disease pathway.
Original languageEnglish
JournalAlzheimer's and Dementia
Issue numberS4
Publication statusPublished - Dec 2021
EventAlzheimer's Association International Conference 2021 - , Virtual
Duration: 26 Jul 202130 Jul 2021


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