Altered HDL Cholesterol Efflux Capacity and LCAT Activity is APOE‐Specific in Alzheimer Disease and Mild Cognitive Impairment Patients

Abstract

AbstractBackgroundHigh‐density lipoproteins (HDL) in circulation perform a crucial role in maintaining cholesterol homeostasis by removing cholesterol from peripheral tissues for excretion. High HDL has been linked with a lower risk of developing Alzheimer’s Disease (AD). However, the concentration of HDL only partially accounts for the variation in the ability of HDL to perform their primary function to efflux cholesterol. Apolipoprotein E (APOE) is the strongest genetic risk factor for AD, and its role in regulating cholesterol is implicated in AD. However, the complex relationship between APOE genotype and the function of peripheral HDL in AD patients remains largely unknown.MethodWe isolated HDL from plasma of 194 age‐ and sex‐matched, ApoE genotyped participants (non‐demented controls, n = 83; mild cognitive impairment, n = 40; AD dementia, n = 71) using two‐step flotation ultracentrifugation, followed by size exclusion chromatography. HDL cholesterol efflux capacity (CEC) and lecithin‐cholesterol acyltransferase (LCAT) activity were measured. We further explored the relationships between HDL functional capacity and cognitive, functional, and imaging scores.ResultRegardless of diagnosis, ApoE3/E4 carriers had significantly lower CEC index (p = 0.003) and LCAT activity (p < 0.001) vs. ApoE3/E3 carriers. When participants were stratified by APOE genotype and diagnosis, ApoE3/E3 MCI patients had significantly lower CEC index than controls (p = 0.042). In contrast, the CEC index of ApoE3/E4 AD patients was paradoxically increased compared to controls (p = 0.016). ApoE3/E3 MCI and AD patients had lower LCAT activity than controls (p = 0.012 and p = 0.004, respectively), but there were no differences in LCAT activity in ApoE3/E4 participants by diagnosis group. LCAT activity was positively correlated with verbal memory score (p = 0.033) and negatively correlated with clinical dementia rating (p = 0.025).ConclusionTo our knowledge, our study revealed for the first time an APOE genotype‐dependent alteration in peripheral HDL functional capacity among AD and MCI patients compared with non‐demented controls and an association between HDL LCAT activity and cognitive and functional scores.