Abstract
Introduction:
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.
Methods:
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.
Results:
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.
Discussion:
Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.
RAS ID
43277
Document Type
Journal Article
Date of Publication
11-2022
Funding Information
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
School
School of Medical and Health Sciences / Centre for Precision Health
Grant Number
NHMRC Number : 1101320, 1157607, 1197190,
Grant Link
http://purl.org/au-research/grants/nhmrc/1101320
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Publisher
Wiley
Comments
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.
https://doi.org/10.1002/alz.12538