High-Density Lipoprotein Cholesterol and Cognitive Function in Older Korean Adults Without Dementia: Apolipoprotein E4 as a Moderating Factor

<b>Background:</b> High-density lipoprotein cholesterol (HDL-C) is known for its cardiovascular and neuroprotective effects, but its association with cognitive function remains unclear, particularly in relation to genetic factors such as apolipoprotein E ε4 (APOE4). We aimed to investigate the association between serum HDL-C levels and cognition and to examine the moderating effect of APOE4 on this relationship. <b>Methods:</b> This cross-sectional study included 196 dementia-free older adults (aged 65-90) recruited from a memory clinic and the community. Cognitive function was assessed across multiple domains using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery. Serum HDL-C levels were measured, and APOE4 genotyping was performed. Multiple linear regression analyses were conducted, adjusting for age, sex, APOE4 status, education, diagnosis, vascular risk, nutritional status, physical activity, and blood biomarkers. <b>Results:</b> Higher HDL-C levels were significantly associated with better episodic memory (B = 0.109, 95% confidence interval [CI]: 0.029-0.189, <i>p</i> = 0.008) and global cognition (B = 0.130, 95% CI: 0.001-0.261, <i>p</i> = 0.049). These associations were significantly moderated by APOE4 status. In APOE4-positive individuals, HDL-C was strongly associated with both episodic memory (B = 0.357, 95% CI: 0.138-0.575, <i>p</i> = 0.003) and global cognition (B = 0.519, 95% CI: 0.220-0.818, <i>p</i> = 0.002), but no such associations were observed in APOE4-negative participants. <b>Conclusions:</b> This study indicates a significant association between serum HDL-C levels and cognitive function, particularly in episodic memory and global cognition, with APOE4 status potentially moderating this relationship. While these findings may suggest a protective role of HDL-C in individuals at increased genetic risk due to APOE4, they should be interpreted with caution given the cross-sectional design. Future longitudinal and mechanistic studies are warranted to clarify causality and potential clinical implications.