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

Author:

Brase LoganORCID,You Shih-Feng,D’Oliveira Albanus RicardoORCID,Del-Aguila Jorge L.ORCID,Dai YaoyiORCID,Novotny Brenna C.ORCID,Soriano-Tarraga Carolina,Dykstra TaiteaORCID,Fernandez Maria VictoriaORCID,Budde John P.ORCID,Bergmann Kristy,Morris John C.,Bateman Randall J.ORCID,Perrin Richard J.ORCID,McDade EricORCID,Xiong Chengjie,Goate Alison M.ORCID,Farlow Martin,Sutherland Greg T.ORCID,Kipnis JonathanORCID,Karch Celeste M.ORCID,Benitez Bruno A.,Harari OscarORCID,

Abstract

AbstractGenetic 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/).

Funder

U.S. Department of Health & Human Services | NIH | National Institute on Aging

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

BrightFocus Foundation

Chan Zuckerberg Initiative

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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