Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers

Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant (APP and PSEN1) and risk-modifying variant (APOE, TREM2 and MS4A) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers. TREM2 oligodendrocytes show a dysregulated autophagy-lysosomal pathway, MS4A microglia have dysregulated complement cascade genes, and APOE epsilon 4 inhibitory neurons display signs of ferroptosis. All cell types have enriched states in autosomal dominant carriers. We leverage differential expression and single-nucleus ATAC-seq to map GWAS signals to effector cell types including the NCK2 signal to neurons in addition to the initially proposed microglia. Overall, our results provide insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity. The data can be explored on the online browser (http://web.hararilab.org/SNARE/).

Automated summary

By performing single-nucleus RNA-sequencing on AD genetic variant carriers, this study reveals the cell-specific effects of variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. The results show dysregulated pathways in specific cell types, such as autophagy-lysosomal pathway in TREM2 oligodendrocytes and complement cascade genes in MS4A microglia. Additionally, the study maps GWAS signals to effector cell types, including neurons in addition to microglia, providing insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity.