Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics

Jessica E Rexach; Yuyan Cheng; Lawrence Chen; Damon Polioudakis; Li-Chun Lin; Vivianne Mitri; Andrew Elkins; Xia Han; Mai Yamakawa; Anna Yin; Daniela Calini; Riki Kawaguchi; Jing Ou; Jerry Huang; Christopher Williams; John Robinson; Stephanie E Gaus; Salvatore Spina; Edward B Lee; Lea T Grinberg; Harry Vinters; John Q Trojanowski; William W Seeley; Dheeraj Malhotra; Daniel H Geschwind

doi:10.1016/j.cell.2024.08.019

Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics

Cell. 2024 Sep 9:S0092-8674(24)00910-3. doi: 10.1016/j.cell.2024.08.019. Online ahead of print.

Authors

Jessica E Rexach¹, Yuyan Cheng², Lawrence Chen², Damon Polioudakis², Li-Chun Lin³, Vivianne Mitri², Andrew Elkins², Xia Han², Mai Yamakawa², Anna Yin², Daniela Calini⁴, Riki Kawaguchi², Jing Ou², Jerry Huang², Christopher Williams², John Robinson⁵, Stephanie E Gaus³, Salvatore Spina³, Edward B Lee⁵, Lea T Grinberg⁶, Harry Vinters², John Q Trojanowski⁵, William W Seeley⁶, Dheeraj Malhotra⁴, Daniel H Geschwind⁷

Affiliations

¹ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: jrexach@mednet.ucla.edu.
² Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
⁴ Neuroscience and Rare Diseases, Roche Pharma Research and Early Development, F. Hoffman-LaRoche Ltd., Basel, Switzerland.
⁵ Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
⁷ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dhg@mednet.ucla.edu.

PMID: 39265576
DOI: 10.1016/j.cell.2024.08.019

Abstract

The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific. Disease-specific cell states represent glial-immune mechanisms and selective neuronal vulnerability impacting layer 5 intratelencephalic neurons in AD, layer 2/3 intratelencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We identify disease-associated gene regulatory networks and cells impacted by causal genetic risk, which differ by disorder. These data illustrate the heterogeneous spectrum of glial and neuronal compositional and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states.

Keywords: KCNH7; MAFG; NFE2L1; NLGN1; OPCML; PDE1C; drug discovery; functional genomics; multi-omics; tauopathy.

Abstract

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