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<p>Extensive research has examined the direct effect of <i>APOE</i> alleles on cognitive decline. However, there is limited investigation into the effect of <i>APOE</i> 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 <i>APOE2</i> 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 <i>APOE2</i> carriers completed the CDT significantly faster compared to common <i>APOE3</i> carriers. Primary analysis identified two lipids (CE 18:3 and TG 56:5) protectively mediated the effect of <i>APOE2</i> on cognitive function, resulting in shorter CDT think-time, ink-time, and total-time; conversely, TG 56:4 deleteriously mediated the effect of <i>APOE2</i>, 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 <i>APOE2</i>. 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 <i>APOE2</i> 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 <i>APOE2</i> on cognition.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • Qingyan Xiang,
  • Judith J. Lok,
  • Nicole Roth,
  • Stacy L. Andersen,
  • Thomas T. Perls,
  • Zeyuan Song,
  • Anatoli I. Yashin,
  • Jonas Mengel-From,
  • Gary J. Patti,
  • Paola Sebastiani

摘要

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.