Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer’s disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs—modules 113 and 114—relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes (ACADVL, TRABD, and VASP) encode proteins that are upregulated in activated microglia in AD.

小胶质细胞功能障碍已被提议为可导致阿尔茨海默氏病（AD）发展的许多细胞机制之一。在这里，使用人类额叶皮层的转录网络图，我们从两个针对脑衰老的队列研究中，识别了与小胶质细胞相关的共表达基因的五个模块，并评估了它们在540名受试者的AD神经病理学特征中的作用。这些转录程序中的两个-模块113和114-与β-淀粉样蛋白的积累有关，而模块5与tau病理学有关。我们在大脑表观基因组数据和两个独立的数据集中复制这些关联。关于tau，我们建议激活小胶质细胞的标志物模块5可能导致tau积累和随后的认知能力下降。我们通过显示三个代表性模块5基因来进一步验证我们的模型（ACADVL，TRABD和VASP）编码在AD的活化小胶质细胞中上调的蛋白质。