Correlations between the NMR Lipoprotein Profile, APOE Genotype, and Cholesterol Efflux Capacity of Fasting Plasma from Cognitively Healthy Elderly Adults

Abstract

Cholesterol efflux capacity (CEC) is of interest given its potential relationship with several important clinical conditions including Alzheimer's disease. The inactivation of the APOE locus in mouse models supports the idea that it is involved in determining the CEC. With that in mind, we examine the impact of the plasma metabolome profile and the APOE genotype on the CEC in cognitively healthy elderly subjects. The study subjects were 144 unrelated healthy individuals. The plasma CEC was determined by exposing cultured mouse macrophages treated with BODIPY-cholesterol to human plasma. The metabolome profile was determined using NMR techniques. Multiple regression was performed to identify the most important predictors of CEC, as well as the NMR features most strongly associated with the APOE genotype. Plasma 3-hydroxybutyrate was the variable most strongly correlated with the CEC (r = 0.365; p = 7.3 × 10-6). Male sex was associated with a stronger CEC (r = -0.326, p = 6.8 × 10-5). Most of the NMR particles associated with the CEC did not correlate with the APOE genotype. The NMR metabolomics results confirmed the APOE genotype to have a huge effect on the concentration of plasma lipoprotein particles as well as those of other molecules including omega-3 fatty acids. In conclusion, the CEC of human plasma was associated with ketone body concentration, sex, and (to a lesser extent) the other features of the plasma lipoprotein profile. The APOE genotype exerted only a weak effect on the CEC via the modulation of the lipoprotein profile. The APOE locus was associated with omega-3 fatty acid levels independent of the plasma cholesterol level.A.R. and S.M. are funded by the Innovative Medicines Initiative 2 Joint Undertaking, which receives support from the European Union Horizon 2020 Research And Innovation Programme (ADAPTED grant no. 115975). S.M.’s research is also funded by the Spanish Ministry of Science and Innovation (PID2020-116303RB-I00/MCIN/AEI/10.13039/501100011033). A.R.’s research is also supported by Instituto de Salud Carlos III (ISCIII) via grants PI13/02434, PI16/01861, PI19/01301, and PI22/01403 Acción Estratégica en Salud, within the framework of the Spanish National R+D+I Plan and funded by the ISCIII-Subdirección General de Evaluación and the European Regional Development Fund (EDRF), as well as by the JPco-fuND-2 “Multinational Research Projects on Personalized Medicine for Neurodegenerative Diseases” PREADAPT project. I.d.R. is supported by a national grant from the Instituto de Salud Carlos III (ISCIII) FI20/00215. M.M. receives support from Instituto de Salud Carlos III (ISCIII) via grant PI19/00335 Acción Estratégica en Salud, within the framework of the Spanish National R+D+I Plan and funded by ISCIII-Subdirección General de Evaluación and the EDRF. AC acknowledges the support of the Instituto de Salud Carlos III (ISCIII) grant Sara Borrell (CD22/00125) and Ministerio de Ciencia e Innovación, Proyectos de Generación de Conocimiento grant PID2021-122473OA-I00. Fundacio ACE researchers research receives support from Grifols, Roche, Janssen, Life Molecular Imaging, Araclon Biotech, Alkahest, Laboratorio de Análisis Echevarne, and IrsiCaixa.Peer reviewe