Alzheimer's disease (AD) is characterized by significant molecular heterogeneity, influenced by a complex interplay of genetic and environmental factors. This study aims to dissect cell-type-specific and spatial transcriptomic alterations in AD, with a particular focus on a subgroup of Down Syndrome (DS) patients afflicted by AD (AD in DS). Our objective is to explore the overlaps and distinctions between sporadic AD (sAD) and AD in DS, thereby providing insights that may bridge the gap between animal models and human AD conditions. We employed spatial transcriptomics (ST) in conjunction with single-nucleus RNA sequencing (snRNA-seq) to analyze cortical tissue samples from individuals in early-stage AD, late-stage AD, and those with AD in DS. Simultaneously, we conducted amyloid plaque and fibril imaging on the same tissue samples, enabling direct correlation of gene expression changes with pathological features. Our comprehensive analysis unveiled significant spatial and cell-type-specific alterations in gene expression across the spectrum of AD pathology. Notably, transcriptomic signatures exhibited remarkable similarities between sAD and AD in DS, suggesting potential commonalities in disease pathways. Furthermore, by integrating amyloid imaging data with ST results, we established direct associations between shifts in gene expression and the spatial distribution of pathological aggregates. These findings highlight the power of spatial transcriptomics in unraveling the intricate molecular mechanisms underpinning AD. Crucially, this study reveals converging molecular pathways between sAD and AD in DS, reinforcing the value of AD in DS as a valuable model for advancing our comprehension of AD pathogenesis at the molecular level.