The pathogenesis of Alzheimer’s disease (AD) is incompletely understood. Single cell and spatial solutions are powerful tools to improve our understanding of disease development and progression by offering insights into how chromatin accessibility and gene expression, specific to cell type and spatial localization, are associated with neuropathology. This app note describes the use of a multiomics approach, combining Chromium Single Cell Multiome ATAC + Gene Expression and Visium Spatial Gene Expression for FFPE plus immunofluorescence protein detection, to resolve the relationship between progressive changes in cell type–specific differential gene expression and plaque burden in the TgCRND8 AD-like mouse model.