Abstract
BACKGROUND: Recent studies have revealed a strong association between the e2 allele of the Apolipoprotein E (APOE2) gene and lipid metabolites. In addition, APOE2 carriers appear to be protected from cognitive decline and Alzheimer's disease. This correlation supports the hypothesis that lipids may mediate the protective effect of APOE2 on cognitive function, thereby providing potential targets for therapeutic intervention. METHODS: We conducted a causal mediation analysis to estimate both the direct effect of APOE2 and its indirect effect through 19 lipid species on cognitive function, using metrics from the digital Clock Drawing Test (CDT) in 1291 Long Life Family Study (LLFS) participants. The CDT metrics included think-time, ink-time, and their sum as total-time to complete the test. RESULTS: Compared to carriers of the common APOE3, APOE2 carriers completed the CDT significantly faster. Two lipids showed protective mediation when elevated in the blood, resulting in shorter CDT think-time (CE 18:3), ink-time (TG 56:5), and total completion time (CE 18:3 and TG 56:5). Elevated TG 56:4, in contrast, showed deleterious mediation resulting in increased ink-time. The combined indirect effect through all lipids significantly mediated 23.1% of the total effect of APOE2 on total-time, reducing it by 0.92s (95% CI: 0.17, 2.00). Additionally, the sum of total indirect effect from all lipids also mediated 27.3% of the total effect on think-time, reducing it by 0.75s, and 13.6% of the total effect on ink-time, reducing it by 0.17s, though these reductions were statistically insignificant. Sensitivity analysis yielded consistent results of the combined indirect effects and total effects and identified additional significant lipid pathways (CE 22:6, TG 51:3, and TG 54:2). CONCLUSIONS: We found that the combined indirect effect through all lipids could mediate 10%-27% of the total direct effect of APOE2 on CDT times. We identified both protective and deleterious lipids, providing insights for new therapeutics targeting those lipids to modulate the protective effects of APOE2 on cognition.