BACKGROUND: Experimental studies have shown that cholesterol-overloaded high-density lipoprotein (HDL) can promote the formation of apolipoprotein E (APOE)-containing HDL, a process correcting the atherogenic function of cholesterol-overloaded HDL. OBJECTIVE: The objective of the study was to explore whether APOE-containing HDL can attenuate the defective impact of cholesterol-overloaded HDL on the development of coronary heart disease (CHD) in humans. METHODS: We measured APOE-HDL cholesterol (APOE-HDLC), HDL cholesterol (HDLC), and HDL particle number in 1112 participants aged 45 to 74 years at baseline in a community-based cohort study. Cholesterol molecules per HDL particle (HDL-C/P ratio) were calculated as the ratio of HDLC to HDL particle number. The ratio of APOE-HDLC to total HDLC (APOE-HDLC/HDLC ratio) was calculated to assess the relative proportion of APOE-HDLC in total HDLC. RESULTS: The HDL-C/P ratio was strongly correlated with APOE-HDLC (partial-r: 0.615). Participants with cholesterol-overloaded HDL (indicated by the highest level of the HDL-C/P ratio) had a high APOE-HDLC/HDLC ratio. Baseline cholesterol-overloaded HDL significantly increased the 10-year risk of incident CHD (hazard ratio = 2.42; 95% confidence interval = 1.06-8.32), but this was attenuated by an increased APOE-HDLC/HDLC ratio. Participants with high HDL-C/P ratio and APOE-HDLC/HDLC ratio had a 42% lower risk, whereas those with a high HDL-C/P ratio and low APOE-HDLC/HDLC ratio had a 2.54-fold higher risk, than those with low HDL-C/P ratio and APOE-HDLC/HDLC ratio after multiple adjustments. CONCLUSION: Cholesterol-overloaded HDLs are related with increased APOE-containing HDL species. APOE-containing HDL was found to attenuate the impact of cholesterol-overloaded HDL on increased incident CHD risk, suggesting that APOE-containing HDL may correct the dysfunction of cholesterol-overloaded HDL. (C) 2017 National Lipid Association. All rights reserved.