The association of high-density lipoprotein cargo proteins with brain volume in older adults in the Atherosclerosis Risk in Communities (ARIC)

Background: High-density lipoprotein (HDL) modulates the blood-brain barrier and cerebrovascular integrity, likely influencing the risk of Alzheimer's disease (AD), neurodegeneration, and cognitive decline. Objective: This study aims to identify HDL protein cargo associated with brain amyloid deposition and brain volume in regions vulnerable to AD pathology in older adults. Methods: HDL was separated from the plasma of 65 non-demented participants of the Atherosclerosis Risk in Communities (ARIC) study using a fast protein liquid chromatography method. HDL cargo proteins were measured using a label-free, untargeted proteomic method based on mass spectrometry and data-independent acquisition. Linear regression with multiple imputations assessed the associations between each HDL cargo protein (log2-transformed) and brain amyloid deposition or temporal-parietal meta-ROI volume, adjusting for covariates. Results: The mean (SD) age of the participants was 76.3 (5.4) years old, 53.8% (35/65) female, 30.8% (20/65) black, and 28.1% (18/64, 1 missing) APOE4 carriers. We found few HDL cargo proteins associated with brain amyloid deposition and considerably more HDL cargo proteins associated with temporal-parietal meta-ROI volume. Two HDL cargo proteins mostly associated with temporoparietal meta-ROI volume were fibrinogen B (FGB) and plasminogen (PLG). A doubling of FGB in HDL was associated with a greater temporoparietal meta-ROI volume of 1638 mm³ (95% CI [688, 2589]). In comparison, a doubling of PLG in HDL was associated with a lower temporoparietal meta-ROI of 2025 mm³ (95% CI [-3669, −1034]). Conclusions: This study suggests that HDL cargo proteins associated with temporal-parietal meta-ROI volume are involved in complement and coagulation pathways.