Associations Between High-Density Lipoprotein Cholesterol Efflux and Brain Grey Matter Volume

<b>Objective:</b> High-density lipoprotein cholesterol efflux function may prevent brain amyloid beta deposition and neurodegeneration. However, the relevance of this finding has not been established in the diverse middle-aged population. <b>Methods:</b> We examined 1826 adults (47% Black adults) who participated in the Dallas Heart Study to determine associations between high-density lipoprotein (HDL) measures and brain structure and function. White matter hyperintensities (WMH) and whole-brain grey matter volume (GMV) were measured using brain MRI, and the Montreal Cognitive Assessment (MoCA) was used to measure neurocognitive function. HDL cholesterol efflux capacity (HDL-CEC) was assessed using fluorescence-labeled cholesterol efflux from J774 macrophages, and HDL particle size measures were assessed using nuclear magnetic resonance (NMR) spectroscopy (LipoScience). Multivariable linear regressions were performed to elucidate associations between HDL-CEC and brain and cognitive phenotypes after adjustment for traditional risk factors such as age, smoking status, time spent in daily physical activity, and education level. <b>Results:</b> Higher HDL-CEC and small HDL particle (HDL-P) concentration were positively associated with higher GMV normalized to total cranial volume (TCV) (GMV/TCV) after adjustment for relevant risk factors (β = 0.078 [95% CI: 0.029, 0.126], <i>p =</i> 0.002, and β = 0.063 [95% CI: 0.014, 0.111], <i>p =</i> 0.012, respectively). Conversely, there were no associations between HDL measures and WMH or MoCA (all <i>p</i> > 0.05). Associations of HDL-CEC and small HDL-P with GMV/TCV were not modified by ApoE-ε4 status or race/ethnicity. <b>Interpretation:</b> Higher HDL cholesterol efflux and higher plasma concentration of small HDL-P were associated with higher GMV/TCV. Additional studies are needed to explore the potential neuroprotective functions of HDL.