Spatial transcriptome-metabolome integration reveals region-specific glial lipid dysregulation linked to Alzheimer's pathology

Abstract

Alzheimer's disease (AD) is associated with disrupted lipid metabolism, but how these abnormalities are organized across brain regions remains unclear. We developed iMIST, a spatial multi-omic approach that integrates metabolomic imaging, histology, and spatial transcriptomics within the same tissue section, and applied it to a mouse model combining progressive amyloid deposition and metabolic vulnerability. In plaque-rich gray matter, microglial activation was associated with Pld4 expression and glycerophospholipid remodeling. In contrast, plaque-sparse white matter showed oligodendrocyte-associated loss of Ugt8a expression and altered galactosylceramide metabolism. Both abnormalities intensified with age, indicating distinct but convergent forms of glial lipid dysregulation across anatomical compartments. These findings show that AD-associated metabolic dysfunction extends beyond plaque microenvironments and demonstrate how spatially integrated transcriptomic, metabolic, and histological measurements can reveal region specific mechanisms of glial vulnerability in neurodegeneration.