A single-cell atlas of the human cortex reveals drivers of transcriptional changes in Alzheimer’s disease in specific cell subpopulations

There is currently little information about how individual cell types contribute to Alzheimer’s disease (AD). Here, we applied single-nucleus RNA-seq (snRNA-seq) on the entorhinal cortex from control and AD brains of twelve individuals, yielding a total of 13,214 high quality nuclei. We detail cell-type-specific gene expression patterns, unveiling how transcriptional changes in specific cell subpopulations contribute to AD. We report that the AD risk gene, APOE, is specifically repressed in AD oligodendrocyte progenitor cells and astrocyte subpopulations, and upregulated in an AD-specific microglial subopulation. Integrating transcription factor regulatory modules with AD risk loci revealed drivers of cell-type-specific fate transitions towards AD. For example, transcription factor EB, a master regulator of lysosomal function, regulates multiple disease genes in a specific AD astrocyte sub-population. These results provide insights into the coordinated control of AD risk genes and their cell-type specific contribution to disease susceptibility and are available at http://adsn.ddnetbio.com.