Document Type

Journal Article

Publication Title

Alzheimer's & Dementia




School of Medical and Health Sciences / Centre for Precision Health




National Health and Medical Research Council

Edith Cowan University

Dementia Australia Research Foundation Scholarship

The Victorian Government's Operational Infrastructure Support Program

Commonwealth. Scientific Industrial and Research Organization [CSIRO]

Mental Health Research institute [MHRI]

National Ageing Research Institute [NARI]

Austin Health, and CogState Ltd

The Dementia Collaborative Research Centre (DCRC2)

The Science and Industry Endowment Fund (SIEF)

Cooperative Research Centre (CRC)

Qatar National Research Fund. Grant Number: NPRP8-061-3-011

NLM. Grant Number: R01 LM012535

NIA. Grant Number: R03AG054936

NIH. Grant Number: U01 AG024904

Grant Number

NHMRC Number : 1101320, 1157607, 1197190,


Wang, T., Huynh, K., Giles, C., Mellett, N. A., Duong, T., Nguyen, A., . . . Meikle, P. J. (2022). APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies. Alzheimer's & Dementia, 18(11), 2151-2166.



The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood.


We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species.


A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively.


Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.



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Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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