Data Sheet 1_APOE4 differentially alters lipid composition in extracellular vesicles from hiPSC-derived neurons of Alzheimer’s disease patients.docx

Targeted lipidomics enabled quantitative profiling of hundreds of individual lipid species across major lipid classes. Univariate and multivariate analyses were applied to identify lipid alterations associated with APOE genotype and AD status.</p>Results<p>APOE4 was associated with differences in lipid composition in neuronal EVs from both healthy and AD donors, suggesting that APOE4 influences EV lipid composition regardless of AD.

Additionally, APOE4/4 carriers with AD exhibited clear, species-specific lipid imbalances. Lower levels of ganglioside GM3 and higher of phosphatidylserine emerged as consistent contributors to the APOE4-associated AD lipid signature, alongside alterations in dihydrosphingomyelin and phosphatidylinositol species linked to membrane integrity, endolysosomal function, and inflammatory pathways. These lipid species were among the strongest variables distinguishing healthy and AD APOE4/4 samples in multivariate analyses.</p>Conclusion<p>These findings specify lipidomic changes in AD related to the APOE4 genotype, and support a model by which APOE4 creates a lipid profile that becomes selectively dysregulated in AD.

By identifying specific lipid species associated with APOE4 and AD, this work provides further evidence that distinct lipidomic signatures are associated with both APOE4 and AD. These findings may contribute to the identification of lipid-based biomarkers and support future investigations into genotype-informed therapeutic strategies, although validation in larger, independent cohorts is required.</p>