APOE Genotype Differentially Modulates Plasma Lipids in Healthy Older Individuals, with Relevance to Brain Health

Article type: Research Article

Authors: Wong, Matthew Wai Kin^a | Braidy, Nady^{a; *} | Crawford, John^a | Pickford, Russell^b | Song, Fei^a | Mather, Karen A.^{a; c} | Attia, John^d | Brodaty, Henry^a | Sachdev, Perminder^{a; e} | Poljak, Anne^{a; b; f}

Affiliations: [a] Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia | [b] Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, Australia | [c] Neuroscience Research Australia, Randwick, Australia | [d] School of Medicine and Public Health, University of Newcastle, Newcastle, Australia | [e] Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia | [f] School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia

Correspondence: [*] Correspondence to: Dr. Nady Braidy, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Barker Street, Randwick NSW 2031, Australia. Tel.: +612 9382 3816; Fax: +612 9382 3774; E-mail: [email protected].

Abstract:  Apolipoprotein E (APOE) genotype is an established genetic risk factor for sporadic Alzheimer’s disease (AD) but the extent to which APOE genotype influences the plasma lipidome is unknown, even though lipids are potential diagnostic or prognostic biomarkers for AD. We quantified plasma lipids using untargeted liquid chromatography coupled mass spectrometry in a total of 152 non-demented participants aged 65–100 years carrying at least one ɛ2 or ɛ4 allele (ɛ2/ɛ2 or ɛ2/ɛ3, n = 38: ɛ4/ɛ3 or ɛ4/ɛ4, n = 38), who were roughly matched to an ɛ3/ɛ3 control by age, sex, and lipid-lowering medication (n = 76). Low density lipoprotein cholesterol levels were genotype dependent (ɛ4/ɛ4> ɛ4/ɛ3> ɛ3/ɛ3> ɛ2/ɛ3> ɛ2/ɛ2). The greatest variation in lipids was related to the ɛ2 isoform, where various lysophosphatidylcholines and all phosphatidylethanolamine (PE) subclasses were elevated relative to ɛ3/ɛ3 and ɛ4 carriers. APOE ɛ4 carriers had reduced phosphatidylinositol relative to ɛ3/ɛ3 and ɛ2 carriers. Logistic regression revealed that ɛ2 carriers were at least 4 times higher odds of being in the highest tertile of PE lipid level relative to ɛ3/ɛ3. The elevation in PE and other phospholipids in ɛ2 carriers may indicate the protective effect of ɛ2 is linked to these phospholipids. Additionally, high baseline PE in cognitively normal participants predicted protection against cognitive decline six years later. Our data suggest substantial modulation of plasma lipids by APOE genotype and therefore indicates possible lipid targets and pathomechanisms involved in AD risk.

Keywords: Alzheimer’s disease, apolipoproteins, lipids, lipidomics, liquid chromatography-mass spectrometry, plasma

DOI: 10.3233/JAD-190524

Journal: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 703-716, 2019