A major obstacle to treating Alzheimer’s disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, a key characteristic of the disease. Here, we present a framework integrating high-quality neuron-type-specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for neurons vulnerable and resistant in AD, identify specific genes and pathways associated with AD neuropathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by amyloid accumulation and aging. We have made all cell-type-specific profiles and functional networks available at http://alz.princeton.edu. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.

治疗阿尔茨海默病 (AD) 的一个主要障碍是我们对选择性神经元脆弱性的分子机制缺乏了解，这是该疾病的一个关键特征。在这里，我们提出了一个框架，该框架将健康小鼠整个生命周期中的高质量神经元类型特异性分子谱与死后人类功能基因组学和数量遗传学数据相结合，我们使用 bacTRAP 生成了该分子谱。我们在分子水平上证明了人-鼠对 AD 中易损和抗性神经元细胞分类的保护，识别与 AD 神经病理学相关的特定基因和通路，并查明选择性脆弱性背后的特定功能基因模块，富含与轴突重塑相关的过程，并受淀粉样蛋白积累和老化的影响。我们已经在 http://alz.princeton.edu 上提供了所有特定于细胞类型的配置文件和功能网络。总的来说，我们的研究提供了一个分子框架，用于理解 AD 中最脆弱神经元内 Aβ、衰老和神经变性之间的复杂相互作用。