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

Logan Brase, Shih-Feng You, Ricardo D’Oliveira Albanus, Jorge L. Del-Aguila, Yaoyi Dai, Brenna C. Novotny, Carolina Soriano-Tarraga, Taitea Dykstra, Maria Victoria Fernandez, John P. Budde, Kristy Bergmann, John C. Morris, Randall J. Bateman, Richard J. Perrin, Eric McDade, Chengjie Xiong, Alison M. Goate, Martin Farlow, Greg T. Sutherland, Jonathan Kipnis, Celeste M. Karch, Bruno A. Benitez and Oscar Harari ()
Additional contact information
Logan Brase: Washington University School of Medicine in St. Louis
Shih-Feng You: Washington University School of Medicine in St. Louis
Ricardo D’Oliveira Albanus: Washington University School of Medicine in St. Louis
Jorge L. Del-Aguila: Merck & Co., Inc.
Yaoyi Dai: Baylor College of Medicine
Brenna C. Novotny: Washington University School of Medicine in St. Louis
Carolina Soriano-Tarraga: Washington University School of Medicine in St. Louis
Taitea Dykstra: Washington University School of Medicine in St. Louis
Maria Victoria Fernandez: Washington University School of Medicine in St. Louis
John P. Budde: Washington University School of Medicine in St. Louis
Kristy Bergmann: Washington University School of Medicine in St. Louis
John C. Morris: Washington University School of Medicine in St. Louis
Randall J. Bateman: Washington University School of Medicine in St. Louis
Richard J. Perrin: Washington University School of Medicine in St. Louis
Eric McDade: Washington University School of Medicine in St. Louis
Chengjie Xiong: Washington University School of Medicine in St. Louis
Alison M. Goate: Icahn School of Medicine at Mount Sinai
Martin Farlow: Indiana University School of Medicine
Greg T. Sutherland: The University of Sydney
Jonathan Kipnis: Washington University School of Medicine in St. Louis
Celeste M. Karch: Washington University School of Medicine in St. Louis
Bruno A. Benitez: Harvard Medical School
Oscar Harari: Washington University School of Medicine in St. Louis

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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 APOEε4 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/ ).

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37437-5

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DOI: 10.1038/s41467-023-37437-5

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