INTRODUCTION: Existing cell-cell communication (CCC) studies of Alzheimer's disease dementia (ADD) using cortical snRNAseq data do not account for the distinct cell-type and gene-expression profiles within cortical layers. Cortical-layer-aware CCC analysis may clarify biological mechanisms associated with ADD and mild cognitive impairment (MCI). METHODS: We applied our recent analytical tool STACCato to identify CCC events associated with ADD and MCI within cortical layers, using a large-scale prefrontal cortex snRNAseq dataset (~1.4M nuclei, n=395) with cortical layers annotated from reference spatial transcriptomics data. RESULTS: We identified ADD/MCI-related CCC events with distinct patterns within cortical layers, including ADD-related interactions involving the known AD risk genes APOE and APP that were detected only in microglia in layer 5, and those with opposite effects of ADD and MCI in layers 5 and 6. DISCUSSION: Our findings on cortical-layer-aware ADD/MCI-related CCC events underscore the importance of spatially-aware genomics studies of AD.