A landscape of the genetic and cellular heterogeneity in Alzheimer disease
A landscape of the genetic and cellular heterogeneity in Alzheimer disease
Abstract BackgroundAlzheimer disease (AD) has substantial genetic, molecular, and cellular heterogeneity associated with its etiology. Much of our current understanding of the main AD molecular events associated with the amyloid hypothesis (APP, PSEN1 and PSEN2) and neuroimmune modulation (TREM2 and MS4A) is based on genetic studies including GWAS. However, the functional genes, downstream transcriptional ramifications, and the cell-type-specific effects of many GWAS loci remain poorly understood. Understanding these effects can point us to the cellular processes involved in AD and uncover potential therapeutic targets. MethodsWe applied a genetic-based approach to our sample selection; our cohort included carriers of AD pathogenic mutations (APP, PSEN1), risk variants in TREM2, and the resilience variant (rs1582763) in the MS4A cluster associated with cerebrospinal fluid (CSF) soluble TREM2 levels. We performed single-nucleus RNA-sequencing (snRNA-seq) of 1,102,459 nuclei from the human parietal cortex of these carriers. Following initial unbiased clustering and cell-type annotation, we performed deep subclustering analysis per cell type to identify unique cellular transcriptional states associated with these genetic variants. We identified differentially expressed genes between cell states and genetic variant carriers/controls, and performed differential cell proportion analyses to determine key differences among these carriers. We analyzed sequencing data from human dorsolateral prefrontal cortex and mouse models to replicate the enrichment of unique cell states in genetic variant carriers. Finally, we leveraged these cell-state differential expression results to link genes in AD GWAS loci to their functional cell types. FindingsWe identified cell-specific expression states influenced by AD genetic factors for neurons and glia. Autosomal dominant AD (ADAD) brains exhibited unique transcriptional states in all cell types. TREM2 variant carrier brains were also enriched for specific microglia and oligodendrocyte subpopulations. Carriers of the resilience MS4A variant were enriched for an altered activated-microglia expression state. We mapped AD GWAS genes to their potential functional cell types, and some, including PLCG2 and SORL1, were expressed in a broader range of brain cell types than previously reported. InterpretationAD pathogenic, risk, or resilience variants are sufficient to alter the transcriptional and cellular landscape of human brains. Overall, our results suggest that the genetic architecture contributes to the cortical cellular heterogeneity associated with disease status, which is a critical factor to consider when designing drug trials and selecting the treatment program for AD patients. Our findings suggest that integrating genetic and single-cell molecular data facilitates our understanding of the heterogeneity of pathways, biological processes and cell types modulated by genetic risk factors for AD. FundingUS National Institutes of Health, Hope Center, Archer foundation, Alzheimer Association, CZI.
Schofield Peter、Brase Logan、You Shih-Feng、Dykstra Taitea、Soriano-Tarraga Carolina、Fernandez Maria Victoria、Budde John P、Bateman Randall J、Xiong Chengjie、Goate Alison、Farlow Martin、Sutherland Greg T、Karch Celeste M、Del-Aguila Jorge L.、Novotny Brenna C、Morris John C、Benitez Bruno A、Chhatwal Jasmeer P.、Dominantly Inherited Alzheimer Network (DIAN)、McDade Eric、Dai Yaoyi、Cruchaga Carlos、Bergmann Kristy、Harari Oscar、Kipnis Jonathan、Perrin Richard J、Chui Helena
Dominantly Inherited Alzheimer Network (DIAN)||Neuroscience Research Australia||School of Medical Sciences, University of New South WalesDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Pathology and Immunology, Washington University School of Medicine||Center for Brain Immunology and Glia (BIG), Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisHope Center for Neurological Disorders, Washington University School of Medicine||Knight Alzheimer Disease Research Center, Washington University School of Medicine||Department of Neurology, Washington University School of Medicine||Dominantly Inherited Alzheimer Network (DIAN)Knight Alzheimer Disease Research Center, Washington University School of Medicine||Division of Biostatistics, Washington University School of MedicineDominantly Inherited Alzheimer Network (DIAN)||Ronald M. Loeb Center for Alzheimer?ˉs Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDominantly Inherited Alzheimer Network (DIAN)||Department of Neurology, Indiana University School of MedicineSchool of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, The University of SydneyDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis||Dominantly Inherited Alzheimer Network (DIAN)Merck & Co., Inc.Department of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisHope Center for Neurological Disorders, Washington University School of Medicine||Knight Alzheimer Disease Research Center, Washington University School of Medicine||Department of Neurology, Washington University School of Medicine||Dominantly Inherited Alzheimer Network (DIAN)Department of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDominantly Inherited Alzheimer Network (DIAN)||Department of Neurology, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Psychiatry, Washington University School of Medicine||Dominantly Inherited Alzheimer Network (DIAN)Baylor College of MedicineDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis||Dominantly Inherited Alzheimer Network (DIAN)Department of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Pathology and Immunology, Washington University School of Medicine||Center for Brain Immunology and Glia (BIG), Washington University in St. LouisHope Center for Neurological Disorders, Washington University School of Medicine||Knight Alzheimer Disease Research Center, Washington University School of Medicine||Department of Neurology, Washington University School of Medicine||Department of Pathology and Immunology, Washington University School of Medicine||Dominantly Inherited Alzheimer Network (DIAN)Dominantly Inherited Alzheimer Network (DIAN)||Alzheimer?ˉs Disease Research Center, Keck School of Medicine at the University of Southern California||Department of Neurology, Keck School of Medicine, University of Southern California
神经病学、精神病学基础医学遗传学分子生物学
Single-nucleus RNA sequencingAlzheimer diseasefunctional genomicsautosomal dominant Alzheimer disease
Schofield Peter,Brase Logan,You Shih-Feng,Dykstra Taitea,Soriano-Tarraga Carolina,Fernandez Maria Victoria,Budde John P,Bateman Randall J,Xiong Chengjie,Goate Alison,Farlow Martin,Sutherland Greg T,Karch Celeste M,Del-Aguila Jorge L.,Novotny Brenna C,Morris John C,Benitez Bruno A,Chhatwal Jasmeer P.,Dominantly Inherited Alzheimer Network (DIAN),McDade Eric,Dai Yaoyi,Cruchaga Carlos,Bergmann Kristy,Harari Oscar,Kipnis Jonathan,Perrin Richard J,Chui Helena.A landscape of the genetic and cellular heterogeneity in Alzheimer disease[EB/OL].(2025-03-28)[2025-05-07].https://www.medrxiv.org/content/10.1101/2021.11.30.21267072.点此复制
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