Integrative brain omics approach highlights sn-1 lysophosphatidylethanolamine in Alzheimer's dementia.

The biology of individual lipid species and their relevance in Alzheimer's disease (AD) remains incompletely understood. To explore the lipidomic biomarkers associated with cognition function and neuropathological changes in AD, we utilize non-targeted mass spectrometry on 316 post-mortem brains from participants in the Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP) cohorts classified as control, asymptomatic AD (AAD), or symptomatic AD (SAD), and integrate the lipidomics data with untargeted proteomics from the same individuals. We find that lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) species are significantly lower in SAD than controls or AAD. Lipid-protein network analyses reveal that LPE/LPC modules are significantly associated with protein modules involved in MAPK/metabolism, post-synaptic density, and cell-ECM interaction pathways, and correlate with better antemortem cognition and reduced AD neuropathology. Particularly, LPE 22:6 [sn-1] is significantly decreased SAD and exerts a pronounced influence on protein changes relevant to neurotransmitter-driven post synaptic changes and plasticity compared to other lysophospholipids species. These findings suggest LPE 22:6 as a potential lipid signature and therapeutic target for AD.