The pathogenesis of Alzheimer’s disease (AD) depends on environmental and heritable factors, with its molecular etiology still unclear. Here we present a spatial transcriptomic (ST) and single-nucleus transcriptomic survey of late-onset sporadic AD and AD in Down syndrome (DSAD). Studying DSAD provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. We identified transcriptomic changes that may underlie cortical layer-preferential pathology accumulation. Spatial co-expression network analyses revealed transient and regionally restricted disease processes, including a glial inflammatory program dysregulated in upper cortical layers and implicated in AD genetic risk and amyloid-associated processes. Cell–cell communication analysis further contextualized this gene program in dysregulated signaling networks. Finally, we generated ST data from an amyloid AD mouse model to identify cross-species amyloid-proximal transcriptomic changes with conformational context.

阿尔茨海默病 （Alzheimer's disease， AD） 的发病机制取决于环境和遗传因素，其分子病因尚不清楚。在这里，我们提出了晚发性散发性 AD 和唐氏综合症 AD （DSAD） 的空间转录组学 （ST） 和单核转录组学调查。研究 DSAD 为增强我们对 AD 转录组的理解提供了机会，有可能弥合遗传小鼠模型和散发性 AD 之间的差距。我们确定了可能是皮质层优先病理积累的基础的转录组学变化。空间共表达网络分析揭示了短暂性和区域限制性的疾病过程，包括上皮层神经胶质炎程序失调，并与 AD 遗传风险和淀粉样蛋白相关过程有关。细胞间通讯分析进一步将该基因程序置于失调的信号网络中。最后，我们从淀粉样蛋白 AD 小鼠模型生成 ST 数据，以识别具有构象背景的跨物种淀粉样蛋白近端转录组变化。