Low-Density Lipoprotein Particle Size Subfractions and Cerebral Amyloidosis

Cerebral beta-amyloidosis (CA) is a condition in which amyloid-β (Aβ) proteins are deposited in the cerebral cortex and is a predictor of Alzheimer's disease (AD). The Aging Brain Study (ABS) investigated risk factors for CA in persons with diabetes and dyslipidemia. In the ABS, we identified that greater levels of LDL cholesterol and lower levels of HDL cholesterol were associated with increased CA. LDL particles comprise multiple species of varying size, density, and protein composition. For example, within a lipoprotein profile characteristic for persons with obesity and diabetic dyslipidemia, larger LDL particles have a greater ApoE to ApoB ratio, enhancing their binding affinity to LDL receptors. The goal of this study was to identify LDL particles that associate with CA in ABS. LDL particle size fractions were measured by ion mobility in plasma samples of 58 participants (40 women and 18 men). CA was assessed using Pittsburgh Compound B index-Positron Emission Tomography (PiB-PET) imaging. Among the LDL subfractions, greater plasma levels of large LDL particles were significantly associated with greater cerebral amyloidosis and lower hippocampal volumes independent of LDL cholesterol or triglyceride levels. Since Aβ is cleared by the LDL receptor family, such as lipoprotein-like receptor 1 (LRP1), one potential mechanism for our findings is competition between ApoE enriched larger LDL particles and brain-derived Aβ on hepatic Aβ clearance and degradation. We conclude that assessing larger LDL particles in persons with atherogenic dyslipidemia may provide a mechanistic biomarker for the extent of CA.