TY - JOUR
T1 - APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species
T2 - analysis of three independent cohort studies
AU - Wang, Tingting
AU - Huynh, Kevin
AU - Giles, Corey
AU - Mellett, Natalie A.
AU - Duong, Thy
AU - Nguyen, Anh
AU - Lim, Wei Ling Florence
AU - Smith, Alex A. T.
AU - Olshansky, Gavriel
AU - Cadby, Gemma
AU - Hung, Joseph
AU - Hui, Jennie
AU - Beilby, John
AU - Watts, Gerald F.
AU - Chatterjee, Pratishtha
AU - Martins, Ian
AU - Laws, Simon M.
AU - Bush, Ashley I.
AU - Rowe, Christopher C.
AU - Villemagne, Victor L.
AU - Ames, David
AU - Masters, Colin L.
AU - Taddei, Kevin
AU - Doré, Vincent
AU - Fripp, Jürgen
AU - Arnold, Matthias
AU - Kastenmüller, Gabi
AU - Nho, Kwangsik
AU - Saykin, Andrew J.
AU - Baillie, Rebecca
AU - Han, Xianlin
AU - Martins, Ralph N.
AU - Moses, Eric K.
AU - Kaddurah-Daouk, Rima
AU - Meikle, Peter J.
N1 - Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - APOEε2
KW - APOEε4
KW - Alzheimer’s disease
KW - lipidomics
KW - lipid species
KW - mass spectrometry
UR - http://www.scopus.com/inward/record.url?scp=85123489503&partnerID=8YFLogxK
UR - https://purl.org/au-research/grants/nhmrc/1101320
UR - https://purl.org/au-research/grants/nhmrc/GNT1157607
UR - https://purl.org/au-research/grants/nhmrc/1197190
U2 - 10.1002/alz.12538
DO - 10.1002/alz.12538
M3 - Article
C2 - 35077012
AN - SCOPUS:85123489503
SN - 1552-5260
VL - 18
SP - 2151
EP - 2166
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 11
ER -