APOE3 Christchurch is associated with sphingolipids recycling and glial lipid remodeling in autosomal dominant Alzheimer’s disease

Alzheimer’s disease is characterized by profound disturbances in brain lipid metabolism, which regulate membrane integrity, connectivity, immune response, and cell survival. However, the mechanisms by which the protective APOE3 Christchurch variant modulates lipid homeostasis in autosomal dominant AD remain poorly understood. Here, we investigated lipid changes in postmortem brains carriers of PSEN1-E280A mutation, including APOE3Ch variant. Using a multimodal approach integrating thin-layer chromatography lipid profiling, enzymatic activity assays, digital PCR, immunofluorescence, flow cytometry, and single-nucleus RNA sequencing, we characterized lipid composition and transcriptional expression in the cerebral cortex. Familial and sporadic AD brains exhibited extensive remodeling of lipid pathways, including depletion of structural phospholipids and marked alterations in sphingolipid metabolism. Notably, APOE3Ch carriers displayed reduced cholesterol and phospholipid content, preservation of ceramide pools, and enrichment of specific ganglioside fractions, accompanied by increased sphingomyelinase activity and coordinated downregulation of genes involved in sphingolipid biosynthesis and remodeling. Single-nucleus transcriptomic analyses further revealed cell-type-specific alterations across glial populations, including reduced pruning of differentiated oligodendrocytes and suppression of lipid metabolic process in astrocytes and microglia. Together, these findings suggest that APOE3Ch promotes a reduced de novo biosynthesis of cholesterol and a distinct sphingolipid metabolic state characterized by enhanced lipid recycling, potentially attenuating lipid-driven neuroinflammatory responses.