Low-density lipoprotein cholesterol modulates amyloid-related entorhinal vulnerability and episodic memory performance in older adults

Introduction Cerebral amyloid-beta (Aβ) burden does not fully explain variation in Alzheimer’s disease (AD)-related brain structure and episodic memory. We examined whether circulating low-density lipoprotein cholesterol (LDL-C) modifies the cross-sectional statistical association between Aβ burden, the entorhinal cortex (EC) thickness and episodic memory performance. Methods Cross-sectional data from 1,253 individuals in the Gwangju Alzheimer’s Disease and Related Dementias cohort (798 cognitively normal, 425 mild cognitive impairment, 30 AD dementia) were analyzed. Primary conditional-process models were adjusted for age, sex, education, body mass index, and HbA1c; clinical diagnosis was examined in sensitivity analyses. HC3 heteroskedasticity-consistent inference was used for the focal interaction, and indirect associations were estimated using 10,000 bootstrap resamples. Results Greater Aβ burden was associated with lower EC thickness (β = −0.0863, p = 0.0012), and EC thickness was positively associated with episodic memory (β = 0.3809, p < 0.001). The unconditional indirect statistical association was supported (β = −0.0329, 95% bias-corrected bootstrap CI [−0.0647, −0.0072]). LDL-C modified the Aβ–EC association (β = −0.0937, HC3 SE = 0.0332, 95% CI [−0.1589, −0.0285], p = 0.0049), although the incremental explanatory magnitude was small (ΔR 2 = 0.0082). The conditional Aβ–EC association was unsupported at approximately 66 mg/dL LDL-C (β = 0.0263, p = 0.583), not statistically supported at approximately 100 mg/dL (β = −0.0639, p = 0.060), and negative at 138 mg/dL (β = −0.1648, p < 0.001). The index of moderated indirect association was supported (β = −0.0357, 95% bias-corrected bootstrap CI [−0.0637, −0.0119]); conditional indirect associations were most clearly supported at higher LDL-C levels. A similar interaction was observed for non-HDL cholesterol, suggesting that the pattern may reflect a broader atherogenic lipid context. Conclusion Circulating LDL-C was associated with modest heterogeneity in the cross-sectional Aβ–EC relationship, with more clearly negative conditional associations observed at higher LDL-C levels. Longitudinal studies are needed to determine the temporal and clinical relevance of these findings.