Plasma high‐density lipoprotein cargo is altered in Alzheimer's disease and is associated with regional brain volume

Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low‐Density Lipoprotein (LDL) cholesterol. On the other hand, High‐Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL‐functionality, which depends upon the HDL‐cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL‐cargo (Cholesterol, ApoA‐I, ApoA‐II, ApoC‐I, ApoC‐III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC‐Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA‐I ratio in AD and HC‐Conv, as well as an increased ApoD/ApoA‐I ratio and a decreased ApoA‐II/ApoA‐I ratio in AD. Higher cholesterol/ApoA‐I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA‐II/ApoA‐I and ApoJ/ApoA‐I ratios were associated with greater cortical grey matter volume (and for ApoA‐II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status‐independent manner, the ApoE/ApoA‐I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data. Remodeling of high‐density lipoprotein (HDL) during disease onset and progression, in which cholesterol and Apolipoprotein D levels are increased while Apolipoprotein A‐II levels are decreased on HDL (left). Additionally, increased cholesterol levels on HDL are associated with increased ventricular volume and decreased grey matter volume, while increased levels of Apolipoprotein A‐II and Apolipoprotein J are associated with increased hippocampal and grey matter volume and reduced ventricular volume (right).