Typical differential single-nucleus gene expression (snRNA-seq) analyses in Alzheimer’s disease (AD) provide fixed snapshots of cellular alterations, making the accurate detection of temporal cell changes challenging. To characterize the dynamic cellular and transcriptomic differences in AD neuropathology, we apply the novel concept of RNA velocity to the study of single-nucleus RNA from the cortex of 60 subjects with varied levels of AD pathology. RNA velocity captures the rate of change of gene expression by comparing intronic and exonic sequence counts. We performed differential analyses to find the significant genes driving both cell type-specific RNA velocity and expression differences in AD, extensively compared these two transcriptomic metrics, and clarified their associations with multiple neuropathologic traits. The results were cross-validated in an independent dataset. Comparison of AD pathology-associated RNA velocity with parallel gene expression differences reveals sets of genes and molecular pathways that underlie the dynamic and static regimes of cell type-specific dysregulations underlying the disease. Differential RNA velocity and its linked progressive neuropathology point to significant dysregulations in synaptic organization and cell development across cell types. Notably, most of the genes underlying this synaptic dysregulation showed increased RNA velocity in AD subjects compared to controls. Accelerated cell changes were also observed in the AD subjects, suggesting that the precocious depletion of precursor cell pools might be associated with neurodegeneration. Overall, this study uncovers active molecular drivers of the spatiotemporal alterations in AD and offers novel insights towards gene- and cell-centric therapeutic strategies accounting for dynamic cell perturbations and synaptic disruptions.

阿尔茨海默病 (AD) 中典型的差异单核基因表达 (snRNA-seq) 分析提供了细胞变化的固定快照，这使得准确检测时间细胞变化具有挑战性。为了表征 AD 神经病理学中的动态细胞和转录组差异，我们将 RNA 速度的新概念应用于来自 60 名具有不同 AD 病理水平的受试者皮层的单核 RNA 的研究。 RNA速度通过比较内含子和外显子序列计数来捕获基因表达的变化率。我们进行了差异分析，以找到驱动 AD 中细胞类型特异性 RNA 速度和表达差异的重要基因，广泛比较这两种转录组指标，并阐明它们与多种神经病理特征的关联。结果在独立数据集中进行了交叉验证。 AD病理相关的RNA速度与平行基因表达差异的比较揭示了构成该疾病的细胞类型特异性失调的动态和静态机制的基因组和分子途径。 RNA 速度差异及其相关的进行性神经病理学表明，不同细胞类型的突触组织和细胞发育存在显着失调。值得注意的是，与对照组相比，AD 受试者中大多数导致这种突触失调的基因显示出 RNA 速度增加。在 AD 受试者中也观察到了加速的细胞变化，这表明前体细胞库的过早耗尽可能与神经退行性疾病有关。总的来说，这项研究揭示了 AD 时空变化的活跃分子驱动因素，并为以基因和细胞为中心的治疗策略提供了新的见解，以解释动态细胞​​扰动和突触破坏。