APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies

Tingting Wang; Kevin Huynh; Corey Giles; Natalie A. Mellett; Thy Duong; Anh Nguyen; Wei Ling Florence Lim; Alex A.T. Smith; Gavriel Olshansky; Gemma Cadby; Joseph Hung; Jennie Hui; John Beilby; Gerald F. Watts; Pratishtha Chatterjee; Ian Martins; Simon M. Laws; Ashley I. Bush; Christopher C. Rowe; Victor L. Villemagne; David Ames; Colin L. Masters; Kevin Taddei; Vincent Doré; Jürgen Fripp; Matthias Arnold; Gabi Kastenmüller; Kwangsik Nho; Andrew J. Saykin; Rebecca Baillie; Xianlin Han; Ralph N. Martins; Eric K. Moses; Rima Kaddurah-Daouk; Peter J. Meikle

doi:10.1002/alz.12538

APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies

Tingting Wang, Kevin Huynh, Corey Giles, Natalie A. Mellett, Thy Duong, Anh Nguyen, Wei Ling Florence Lim, Alex A.T. Smith, Gavriel Olshansky, Gemma Cadby, Joseph Hung, Jennie Hui, 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, Kevin Taddei, Vincent Doré, Jürgen Fripp, Matthias Arnold, Gabi Kastenmüller, Kwangsik Nho, Andrew J. Saykin, Rebecca Baillie, Xianlin Han, Ralph N. Martins, Eric K. Moses, Rima Kaddurah-Daouk, Peter J. Meikle

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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.

Original language	English
Pages (from-to)	2151-2166
Number of pages	16
Journal	Alzheimer's & dementia : the journal of the Alzheimer's Association
Volume	18
Issue number	11
Early online date	25 Jan 2022
DOIs	https://doi.org/10.1002/alz.12538
Publication status	Published - Nov 2022

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10.1002/alz.12538Licence: CC BY-NC

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Wang, T., Huynh, K., Giles, C., Mellett, N. A., Duong, T., Nguyen, A., Lim, W. L. F., Smith, A. A. T., Olshansky, G., Cadby, G., Hung, J., Hui, J., Beilby, J., Watts, G. F., Chatterjee, P., Martins, I., Laws, S. M., Bush, A. I., Rowe, C. C., ... 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 : the journal of the Alzheimer's Association, 18(11), 2151-2166. https://doi.org/10.1002/alz.12538

@article{1cc7d355e3c74e5d84650277783e9e22,

title = "APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies",

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.",

author = "Tingting Wang and Kevin Huynh and Corey Giles and Mellett, {Natalie A.} and Thy Duong and Anh Nguyen and Lim, {Wei Ling Florence} and Smith, {Alex A.T.} and Gavriel Olshansky and Gemma Cadby and Joseph Hung and Jennie Hui and John Beilby and Watts, {Gerald F.} and Pratishtha Chatterjee and Ian Martins and Laws, {Simon M.} and Bush, {Ashley I.} and Rowe, {Christopher C.} and Villemagne, {Victor L.} and David Ames and Masters, {Colin L.} and Kevin Taddei and Vincent Dor{\'e} and J{\"u}rgen Fripp and Matthias Arnold and Gabi Kastenm{\"u}ller and Kwangsik Nho and Saykin, {Andrew J.} and Rebecca Baillie and Xianlin Han and Martins, {Ralph N.} and Moses, {Eric K.} and Rima Kaddurah-Daouk and Meikle, {Peter J.}",

year = "2022",

month = nov,

doi = "10.1002/alz.12538",

language = "English",

volume = "18",

pages = "2151--2166",

journal = "Alzheimer's & dementia : the journal of the Alzheimer's Association",

issn = "1552-5260",

publisher = "Academic Press",

number = "11",

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Wang, T, Huynh, K, Giles, C, Mellett, NA, Duong, T, Nguyen, A, Lim, WLF, Smith, AAT, Olshansky, G, Cadby, G , Hung, J , Hui, J , Beilby, J , Watts, GF, Chatterjee, P, Martins, I, Laws, SM, Bush, AI, Rowe, CC, Villemagne, VL, Ames, D, Masters, CL, Taddei, K, Doré, V, Fripp, J, Arnold, M, Kastenmüller, G, Nho, K, Saykin, AJ, Baillie, R, Han, X, Martins, RN, Moses, EK, Kaddurah-Daouk, R & Meikle, PJ 2022, 'APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies', Alzheimer's & dementia : the journal of the Alzheimer's Association, vol. 18, no. 11, pp. 2151-2166. https://doi.org/10.1002/alz.12538

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85123489503&partnerID=8YFLogxK

U2 - 10.1002/alz.12538

DO - 10.1002/alz.12538

M3 - Article

C2 - 35077012

SN - 1552-5260

VL - 18

SP - 2151

EP - 2166

JO - Alzheimer's & dementia : the journal of the Alzheimer's Association

JF - Alzheimer's & dementia : the journal of the Alzheimer's Association

IS - 11

ER -

APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies

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The Busselton Family Heart Study

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APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies

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The Busselton Family Heart Study

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