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

Abstract

Objective: 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. Methods: 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. Results: 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], p = 0.002, and β = 0.063 [95% CI: 0.014, 0.111], p = 0.012, respectively). Conversely, there were no associations between HDL measures and WMH or MoCA (all p > 0.05). Associations of HDL-CEC and small HDL-P with GMV/TCV were not modified by ApoE-ε4 status or race/ethnicity. Interpretation: 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.

Keywords: brain grey matter; high-density lipoprotein cholesterol; neurocognitive function; neurodegeneration.

Figure 1

Study Flow Chart (CVD: cardiovascular disease; DHS: Dallas Heart Study; MRI: magnetic resonance imaging; NMR: nuclear magnetic resonance; MoCA: Montreal Cognitive Assessment).

Figure 2

Cubic Spline of HDL-CEC with GM Volume. Restricted cubic spline and 95% confidence bands relating the average HDL-CEC with GMV in the whole cohort after adjustment for age, sex, race, MVPA, smoking status, education levels, and the average across DHS-1 and DHS-2 of BMI, systolic BP, plasma glucose, eGFR, and average HDL-C from both DHS phases. (BMI: body mass index; CEC: cholesterol efflux capacity; eGFR: estimated glomerular filtration rate; GMV: grey matter volume; HDL: high-density lipoprotein; MVPA: moderate-to-vigorous physical activity; BP: blood pressure; β: standardized regression coefficient.)