|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Mathys, H, Davila-Velderrain, J, Peng, Z, Gao, F, Mohammadi, S, Young, JZ, Menon, M, He, L, Abdurrob, F, Jiang, X, Martorell, AJ, Ransohoff, RM, Hafler, BP, Bennett, DA, Kellis, M, Tsai, L-H|
|Date Published||2019 May 01|
Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, the molecular and cellular complexity of which remains poorly understood. Here, we profiled and analysed 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.