Alzheimer's disease (AD) affects one in eight individuals over 65 and poses an immense societal challenge. AD pathology is characterized by the formation of beta-amyloid plaques and Tau tangles in the brain. While some disease-modifying treatments targeting beta-amyloid are emerging, the exact chain of events underlying the pathogenesis of this disease remains unclear. Brain lipids have long been implicated in AD pathology, though their role in AD pathogenesis remains not fully resolved. Significant advancements in mass spectrometry imaging (MSI) allow to detail spatial lipid regulations in biological tissues at the low um scale. In this issue, Huang et al. resolve spatial lipid patterns in human AD brain and genetic mouse models using desorption electrospray ionization (DESI)-based MSI integrated with other spatial techniques such as imaging mass cytometry of correlative protein signatures. Those spatial multiomics experiments identify plaque-associated lipid regulations that are dependent on progressing plaque pathology in both mouse models and the human brain. Of those lipid species, particularly pro-inflammatory lysophospholipids have been implicated in AD pathology through their interaction with both aggregating Aβ and microglial activation through lipid sensing surface receptors. Together, this study provides further insight into how brain lipid homeostasis is linked to progressing AD pathology, and thereby highlights the potential of MSI-based spatial lipidomics as an emerging spatial biology technology for biomedical research.