# The role of lipids in the effect of APOE2 on cognitive function: a causal mediation analysis

## TL;DR

This study explores how specific lipid molecules mediate the effect of the APOE2 gene variant on cognitive function, identifying potential therapeutic targets.

## Contribution

The study identifies seven lipid species that mediate the protective and harmful effects of APOE2 on cognitive performance.

## Key findings

- APOE2 carriers performed the Clock Drawing Test faster than APOE3 carriers.
- Two lipids (CE 18:3 and TG 56:5) protectively mediated APOE2's effect on cognitive function.
- TG 56:4 had a deleterious effect, increasing ink-time in the test.

## Abstract

Extensive research has examined the direct effect of APOE alleles on cognitive decline. However, there is limited investigation into the effect of APOE that is explained or mediated through molecular pathways, such as lipids. In this study, we performed a causal mediation analysis to estimate both the direct effect of APOE2 and its indirect effect through 24 lipid species on cognitive function, measured from the digital Clock Drawing Test (CDT) in 1228 Long Life Family Study (LLFS) participants. Results showed that APOE2 carriers completed the CDT significantly faster compared to common APOE3 carriers. Primary analysis identified two lipids (CE 18:3 and TG 56:5) protectively mediated the effect of APOE2 on cognitive function, resulting in shorter CDT think-time, ink-time, and total-time; conversely, TG 56:4 deleteriously mediated the effect of APOE2, resulting in increased ink-time. Secondary analysis yielded consistent results and identified four additional significant lipid pathways (DG 38:5, TG 51:3, TG 56:1, TG 56:2) that mediated the effect of APOE2. The combined indirect effect in the primary analysis contributed 15%–30% mediated proportion on CDT times, though such mediated proportion did not reach statistical significance. Overall, our analysis identified seven lipid species that significantly mediate the effect of APOE2 on cognitive performance. These lipids represent distinct lipid pathways, including both protective and deleterious mediation effects. Our findings offer insights for new therapeutics targeting those lipids to enhance the protective effects of APOE2 on cognition.

The online version contains supplementary material available at 10.1007/s10654-025-01310-0.