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

doi:10.1016/j.cell.2024.08.019

. 2024 Oct 3;187(20):5753-5774.e28.

doi: 10.1016/j.cell.2024.08.019. Epub 2024 Sep 11.

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

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
PMCID: PMC12017262 (available on 2025-10-03)
DOI: 10.1016/j.cell.2024.08.019

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

Jessica E Rexach et al. Cell. 2024.

. 2024 Oct 3;187(20):5753-5774.e28.

doi: 10.1016/j.cell.2024.08.019. Epub 2024 Sep 11.

Authors

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
PMCID: PMC12017262 (available on 2025-10-03)
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.

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Conflict of interest statement

Declaration of interests D.H.G. has received research funding from Hoffman-LaRoche for this project. D.C. is a full-time employee of F. Hoffmann-La Roche, Basel, Switzerland. During the study period, D.M. was a full-time employee of F. Hoffmann-La Roche, Basel, Switzerland, and is currently a full-time employee of Biogen, Cambridge, MA, USA.

Update of

Disease-specific selective vulnerability and neuroimmune pathways in dementia revealed by single cell genomics.
Rexach JE, Cheng Y, Chen L, Polioudakis D, Lin LC, Mitri V, Elkins A, Yin A, Calini D, Kawaguchi R, Ou J, Huang J, Williams C, Robinson J, Gaus SE, Spina S, Lee EB, Grinberg LT, Vinters H, Trojanowski JQ, Seeley WW, Malhotra D, Geschwind DH. Rexach JE, et al. bioRxiv [Preprint]. 2023 Sep 30:2023.09.29.560245. doi: 10.1101/2023.09.29.560245. bioRxiv. 2023. Update in: Cell. 2024 Oct 3;187(20):5753-5774.e28. doi: 10.1016/j.cell.2024.08.019. PMID: 37808727 Free PMC article. Updated. Preprint.

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References

1. Bahia VS, Takada LT, and Deramecourt V. (2013). Neuropathology of frontotemporal lobar degeneration: a review. Dement. Neuropsychol 7, 19–26. 10.1590/S1980-57642013DN70100004. - DOI - PMC - PubMed
1. Chung DC, Roemer S, Petrucelli L, and Dickson DW (2021). Cellular and pathological heterogeneity of primary tauopathies. Mol. Neurodegener 16, 57. 10.1186/s13024-021-00476-x. - DOI - PMC - PubMed
1. Young JJ, Lavakumar M, Tampi D, Balachandran S, and Tampi RR (2018). Frontotemporal dementia: latest evidence and clinical implications. Ther. Adv. Psychopharmacol 8, 33–48. 10.1177/2045125317739818. - DOI - PMC - PubMed
1. Boeve BF, Boxer AL, Kumfor F, Pijnenburg Y, and Rohrer JD (2022). Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations. Lancet Neurol. 21, 258–272. 10.1016/S1474-4422(21)00341-0. - DOI - PubMed
1. Fu H, Hardy J, and Duff KE (2018). Selective vulnerability in neurodegenerative diseases. Nat. Neurosci 21, 1350–1358. 10.1038/s41593-018-0221-2. - DOI - PMC - PubMed

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[1] Bahia VS, Takada LT, and Deramecourt V. (2013). Neuropathology of frontotemporal lobar degeneration: a review. Dement. Neuropsychol 7, 19–26. 10.1590/S1980-57642013DN70100004. - DOI - PMC - PubMed

[2] Bahia VS, Takada LT, and Deramecourt V. (2013). Neuropathology of frontotemporal lobar degeneration: a review. Dement. Neuropsychol 7, 19–26. 10.1590/S1980-57642013DN70100004. - DOI - PMC - PubMed

[3] Chung DC, Roemer S, Petrucelli L, and Dickson DW (2021). Cellular and pathological heterogeneity of primary tauopathies. Mol. Neurodegener 16, 57. 10.1186/s13024-021-00476-x. - DOI - PMC - PubMed

[4] Chung DC, Roemer S, Petrucelli L, and Dickson DW (2021). Cellular and pathological heterogeneity of primary tauopathies. Mol. Neurodegener 16, 57. 10.1186/s13024-021-00476-x. - DOI - PMC - PubMed

[5] Young JJ, Lavakumar M, Tampi D, Balachandran S, and Tampi RR (2018). Frontotemporal dementia: latest evidence and clinical implications. Ther. Adv. Psychopharmacol 8, 33–48. 10.1177/2045125317739818. - DOI - PMC - PubMed

[6] Young JJ, Lavakumar M, Tampi D, Balachandran S, and Tampi RR (2018). Frontotemporal dementia: latest evidence and clinical implications. Ther. Adv. Psychopharmacol 8, 33–48. 10.1177/2045125317739818. - DOI - PMC - PubMed

[7] Boeve BF, Boxer AL, Kumfor F, Pijnenburg Y, and Rohrer JD (2022). Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations. Lancet Neurol. 21, 258–272. 10.1016/S1474-4422(21)00341-0. - DOI - PubMed

[8] Boeve BF, Boxer AL, Kumfor F, Pijnenburg Y, and Rohrer JD (2022). Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations. Lancet Neurol. 21, 258–272. 10.1016/S1474-4422(21)00341-0. - DOI - PubMed

[9] Fu H, Hardy J, and Duff KE (2018). Selective vulnerability in neurodegenerative diseases. Nat. Neurosci 21, 1350–1358. 10.1038/s41593-018-0221-2. - DOI - PMC - PubMed

[10] Fu H, Hardy J, and Duff KE (2018). Selective vulnerability in neurodegenerative diseases. Nat. Neurosci 21, 1350–1358. 10.1038/s41593-018-0221-2. - DOI - PMC - PubMed

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

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

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