Dysregulated Lipids in Alzheimer’s Disease: Insights into Biological Pathways through LC–MS/MS Analysis of Human Brain Tissues

Alzheimer's Disease (AD), the leading cause of dementia, is characterized by complex pathological mechanisms that extend beyond amyloid-β plaques and tau tangles. This study investigates the dysregulation of lipids with a focus on phospholipids and sphingolipids, in human post-mortem AD brain tissue using lipidomics methodology. By employing a ZIC-HILIC LC-MS/MS platform, the lipidome of AD (<i>N</i> = 18) was compared to the control (<i>N</i> = 18). Out of 45 quantified lipid classes, 16 belonging to phospholipids and sphingolipids group are differentially expressed (<i>p</i> < 0.05; <i>q</i> < 0.05) in AD compared to control. Key findings include the upregulation of phosphatidylcholine (PC), phosphatidylglycerol (PG), ganglioside GD2 (GD2), phosphatidylinositol (PI), phosphatidylserine (PS), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingomyelin (phSM), along with the downregulation of ganglioside GD1a in AD. The targeted analysis revealed that ganglioside GD1b exhibits a higher abundance than ganglioside GD1a across all sample groups. System biology analysis revealed that dysregulated lipids impact critical pathways, including glycerophospholipid biosynthesis and sphingolipid metabolism. Additionally, proteomics analysis on the samples showed that proteins such as Amyloid-β precursor protein, pleckstrin homology and SEC7 domain-containing protein 2 (PSD2), and RAC-gamma serine/threonine-protein kinase (AKT) play a role in phospholipid and sphingolipid dysregulation observed in AD. The dysregulated lipids are predicted to be involved in neuronal cell death, necrosis, and apoptosis, advancing our understanding of AD pathogenesis. The study highlights phospholipids and sphingolipids as promising biomarkers and potential therapeutic targets for AD, paving the way for possible diagnostic tools and personalized treatments.