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

Sep 28, 2026

Uploaded by Liam

Extensive research has examined how APOE alleles directly affect cognitive decline, but fewer studies clarify how these effects are mediated through molecular pathways such as lipids. This study applies causal mediation analysis to estimate both direct and lipid-mediated effects of APOE2 on cognition using digital Clock Drawing Test (CDT) data from 1,228 Long Life Family Study participants. Results identify protective mediation by CE 18:3 and TG 56:5, and deleterious mediation by TG 56:4, with additional significant lipid pathways also supporting mediation.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Introduction

Methods

Participants

Long Life Family Study (LLFS)

European Journal of Epidemiology (2025) 40:1469–1480 [https://doi.org/10.1007/s10654-025-01310-0](https://doi.org/10.1007/s10654-025-01310-0) NEURO-EPIDEMIOLOGY The role of lipids in the effect of APOE2 on cognitive function: a causal mediation analysis Qingyan Xiang1 · Judith J. Lok2 · Nicole Roth3 · Stacy L. Andersen3 · Thomas T. Perls3 · Zeyuan Song4,10 · Anatoli I. Yashin5 · Jonas Mengel-From6 · Gary J. Patti7,8,9 · Paola Sebastiani4,10,11 Received: 20 January 2025 / Accepted: 8 September 2025 / Published online: 3 October 2025 © The Author(s) 2025 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 ofAPOE2 on cognition. Keywords Apolipoprotein E · Cognition · Longevity · Mediation analysis · Observational data 􀀍 1 2 3 4 5 Qingyan Xiang [qingyan.xiang@vumc.org](qingyan.xiang@vumc.org) Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37235, USA Department of Mathematics and Statistics, Boston University, Boston, MA, USA Section of Geriatrics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, USA 6 Department of Public Health, University of Southern Denmark, Odense, Denmark 7 Department of Genetics, Washington University in St. Louis, St. Louis, MO, USA 8 Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA 9 Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA 10 School of Medicine, Tufts University, Boston, MA, USA 11 Data Intensive Study Center, Tufts University, Boston, MA, USA Introduction The apolipoprotein E (APOE) gene, a crucial gene in lipid metabolism, has been extensively studied for its association with cognitive function and late-onset Alzheimer’s Disease (AD) [1–4] . The APOE gene has three well-characterized alleles—e2, e3, and e4—that are defined by combinations of the Single Nucleotide Polymorphisms (SNPs) rs7412 andrs429358. Among these alleles, the e3 allele is the most common in Non-Hispanic and White individuals and is considered neutral. The e4 allele is considered as a major genetic determinant for AD risk and cognitive decline [5–7], and the e2 allele is associated with increased human longevit

FAQs

What cognitive measure is used to assess APOE2-related effects in this study?

Cognitive function is measured with the digital Clock Drawing Test (CDT), using think-time, ink-time, and total-time derived from the test.

How was the mediation effect of lipids on APOE2 evaluated?

A causal mediation analysis was performed to estimate the direct effect of APOE2 and the indirect effects transmitted through 24 lipid species.

Which lipids were reported as protective or deleterious mediators?

Protective mediation was identified for CE 18:3 and TG 56:5, while TG 56:4 showed deleterious mediation, increasing ink-time.

Sep 28, 2026

Uploaded by Liam