Hippocampal mediation in the lipid–Alzheimer's disease pathway: A high‐dimensional mediation analysis stratified by APOE and sex
TL;DR
The left hippocampus is a critical mediator linking specific plasma lipids to AD progression, with an additional vascular pathway via white matter hyperintensities emerging after comorbidity adjustment, supporting a dual neurodegenerative–vascular pathway.
Abstract
Abstract INTRODUCTION Systemic lipid dysregulation is a modifiable risk factor for Alzheimer's disease (AD), yet the neuroanatomic pathways through which specific lipids influence AD progression remain poorly delineated. We investigated whether brain structure mediates the relationship between plasma lipids and AD progression, and whether this pathway is modified by apolipoprotein E (APOE) genotype and sex.
Methods
This retrospective cohort study included 1019 non‐demented participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Baseline plasma lipidomics (781 species) and subsequent T1 magnetic resonance imaging (MRI)–derived brain volumes and cortical thickness (198 features) were analyzed. Cox models identified lipids and brain regions associated with time‐to‐AD progression. High‐dimensional mediation analysis (HIMA) was employed to identify significant mediators, followed by stratified analyses by APOE ε4 carrier status and gender and sensitivity analyses adjusting for cerebrospinal fluid (CSF) biomarkers and comorbidities.
Results
Thirty‐five lipids were associated with AD progression. High‐dimensional mediation analysis across all 198 imaging features uniquely identified left hippocampus volume as the sole significant mediator for 14 specific lipids, including lysophosphatidylcholines and phosphoinositols. Stratified analyses revealed that this mediation pathway was predominantly driven by APOE ε4 carriers. Furthermore, gender differences were observed: female participants exhibited a more isolated indirect effect through the hippocampus for key lipids, whereas male participants often showed concurrent direct and indirect effects. Sensitivity analyses confirmed robustness after adjusting for CSF amyloid beta (Aβ)42/phosphorylated tau (p‐tau) and revealed white matter hyperintensities as an additional mediator when accounting for comorbidities, supporting a dual neurodegenerative–vascular pathway.
Discussion
The left hippocampus is a critical mediator linking specific plasma lipids to AD progression, with an additional vascular pathway via white matter hyperintensities emerging after comorbidity adjustment. This pathway is strongly modified by both APOE genotype and sex, highlighting the potential for precision‐medicine interventions targeting lipid metabolism to preserve brain structure and slow disease progression, particularly in genetically susceptible individuals.