Single-cell Atlas Reveals Correlates of High Cognitive Function, Dementia, and Resilience to Alzheimer's Disease Pathology

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Sep 29

PMID 37774677

Authors

Hansruedi Mathys

Zhuyu Peng

Carles A Boix

Matheus B Victor

Noelle Leary

Sudhagar Babu

Ghada Abdelhady

Xueqiao Jiang

Ayesha P Ng

Kimia Ghafari

Alexander K Kunisky

Julio Mantero

Kyriaki Galani

Vanshika N Lohia

Gabrielle E Fortier

Yasmine Lotfi

Jason Ivey

Hannah P Brown

Pratham R Patel

Nehal Chakraborty

Jacob I Beaudway

Elizabeth J Imhoff

Cameron F Keeler

Maren M McChesney

Haishal H Patel

Sahil P Patel

Megan T Thai

David A Bennett

Manolis Kellis

Li-Huei Tsai

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.

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References

Hodge R, Bakken T, Miller J, Smith K, Barkan E, Graybuck L . Conserved cell types with divergent features in human versus mouse cortex. Nature. 2019; 573(7772):61-68. PMC: 6919571. DOI: 10.1038/s41586-019-1506-7. View

Wilson R, Boyle P, Yu L, Barnes L, Sytsma J, Buchman A . Temporal course and pathologic basis of unawareness of memory loss in dementia. Neurology. 2015; 85(11):984-91. PMC: 4567465. DOI: 10.1212/WNL.0000000000001935. View

Butler A, Hoffman P, Smibert P, Papalexi E, Satija R . Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018; 36(5):411-420. PMC: 6700744. DOI: 10.1038/nbt.4096. View

Robinson M, McCarthy D, Smyth G . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009; 26(1):139-40. PMC: 2796818. DOI: 10.1093/bioinformatics/btp616. View

Bennett D, Buchman A, Boyle P, Barnes L, Wilson R, Schneider J . Religious Orders Study and Rush Memory and Aging Project. J Alzheimers Dis. 2018; 64(s1):S161-S189. PMC: 6380522. DOI: 10.3233/JAD-179939. View

Sadick J, ODea M, Hasel P, Dykstra T, Faustin A, Liddelow S . Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer's disease. Neuron. 2022; 110(11):1788-1805.e10. PMC: 9167747. DOI: 10.1016/j.neuron.2022.03.008. View

Satija R, Farrell J, Gennert D, Schier A, Regev A . Spatial reconstruction of single-cell gene expression data. Nat Biotechnol. 2015; 33(5):495-502. PMC: 4430369. DOI: 10.1038/nbt.3192. View

Grodstein F, Wang T, Leurgans S, Wilson R, Bennett D . Modifiable psychosocial risk factors and delayed onset of dementia in older populations: analysis of two prospective US cohorts. BMJ Open. 2022; 12(4):e059317. PMC: 8981290. DOI: 10.1136/bmjopen-2021-059317. View

Wagner M, Wilson R, Leurgans S, Boyle P, Bennett D, Grodstein F . Quantifying longitudinal cognitive resilience to Alzheimer's disease and other neuropathologies. Alzheimers Dement. 2022; 18(11):2252-2261. PMC: 10119432. DOI: 10.1002/alz.12576. View

10.

Vanlandewijck M, He L, Mae M, Andrae J, Ando K, Del Gaudio F . A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018; 554(7693):475-480. DOI: 10.1038/nature25739. View

11.

Oppikofer M, Sagolla M, Haley B, Zhang H, Kummerfeld S, Sudhamsu J . Non-canonical reader modules of BAZ1A promote recovery from DNA damage. Nat Commun. 2017; 8(1):862. PMC: 5636791. DOI: 10.1038/s41467-017-00866-0. View

12.

Giurgiu M, Reinhard J, Brauner B, Dunger-Kaltenbach I, Fobo G, Frishman G . CORUM: the comprehensive resource of mammalian protein complexes-2019. Nucleic Acids Res. 2018; 47(D1):D559-D563. PMC: 6323970. DOI: 10.1093/nar/gky973. View

13.

Johnson E, Dammer E, Duong D, Ping L, Zhou M, Yin L . Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020; 26(5):769-780. PMC: 7405761. DOI: 10.1038/s41591-020-0815-6. View

14.

Welch G, Boix C, Schmauch E, Davila-Velderrain J, Victor M, Dileep V . Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration. Sci Adv. 2022; 8(39):eabo4662. PMC: 9519048. DOI: 10.1126/sciadv.abo4662. View

15.

Xiao M, Xu D, Craig M, Pelkey K, Chien C, Shi Y . NPTX2 and cognitive dysfunction in Alzheimer's Disease. Elife. 2017; 6. PMC: 5404919. DOI: 10.7554/eLife.23798. View

16.

Leng K, Li E, Eser R, Piergies A, Sit R, Tan M . Molecular characterization of selectively vulnerable neurons in Alzheimer's disease. Nat Neurosci. 2021; 24(2):276-287. PMC: 7854528. DOI: 10.1038/s41593-020-00764-7. View

17.

Kari V, Mansour W, Raul S, Baumgart S, Mund A, Grade M . Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. EMBO Rep. 2016; 17(11):1609-1623. PMC: 5090703. DOI: 10.15252/embr.201642352. View

18.

Fujita M, Gao Z, Zeng L, McCabe C, White C, Ng B . Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain. Nat Genet. 2024; 56(4):605-614. DOI: 10.1038/s41588-024-01685-y. View

19.

Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park S . SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell. 2008; 135(5):907-18. PMC: 2853975. DOI: 10.1016/j.cell.2008.10.025. View

20.

Serrano-Pozo A, Frosch M, Masliah E, Hyman B . Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2012; 1(1):a006189. PMC: 3234452. DOI: 10.1101/cshperspect.a006189. View