Gao, FanKellis, ManolisMathys, HansruediDavila-Velderrain, JosePeng, ZhuyuMohammadi, ShahinYoung, JennieMenon, MadhviHe, LiangAbdurrob, FatemaJiang, XueqiaoMartorell, AnthonyRansohoff, RichardHafler, BrianBennett, DavidTsai, Li-Huei2022-08-032019-05-01Mathys, Hansruedi, Jose Davila-Velderrain, Zhuyu Peng, Fan Gao, Shahin Mohammadi, Jennie Z. Young, Madhvi Menon, Liang He, Fatema Abdurrob, Xueqiao Jiang, Anthony J. Martorell, Richard M. Ransohoff, Brian P. Hafler, David A. Bennett, Manolis Kellis, and Li-Huei Tsai. 2019. Single-Cell Transcriptomic Analysis of Alzheimer’s Disease. Nature 570: 332–337.0028-08361476-4687https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37372930Thank you in advance for the assistance.Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder whose molecular and cellular complexity remains poorly understood. Here, we profiled and analyzed 80,660 single-nucleus transcriptomes from prefrontal cortex of 48 individuals with varying degrees of AD pathology. We identified transcriptionally-distinct subpopulations across six major brain cell-types, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest AD-associated changes appeared early in pathological progression and were highly cell type-specific, whereas genes upregulated in late-stage were common across cell types and primarily involved in global stress response. Surprisingly, we found an overrepresentation of female cells in AD-associated subpopulations, and substantially different transcriptional responses between sexes in multiple cell types including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting a key role in AD pathophysiology. Our single-cell transcriptomic resource provides a first blueprint for interrogating the molecular underpinnings and cellular basis of AD.en-USMultidisciplinaryJournal Article2022-08-0310.1038/s41586-019-1195-2