ArticleCell2022
Cholesterol and matrisome pathways dysregulated in astrocytes and microglia.
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Article in Cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 261 papers, 3 of them syntheses that pooled it.
0numbers the graph read from it
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261citing papers in PubMed, 3 pooled it
43.3field-weighted citation impact, top 1% of its field
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Who cites it
261 citing papers in PubMed, 3 syntheses or guidelines pooled it, 378 citations in OpenAlex.
- A cell-type-resolved meta-analysis reveals glial DNA methylation changes associated with aging and Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Pooled it
- The role of APOE ε4 in modulating the relationship between non-genetic risk factors and dementia: a system review and meta-analysis.Journal of neurology · 2025Pooled it
- Pooled it
- Cell-based polygenic risk scores predict clinical progression and prioritize network-based therapeutic targets in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Discovery of a brain penetrant NLRP3 inflammasome inhibitor that reduces neuropathic pain in mice.European journal of medicinal chemistry · 2026Article
- Human iPSC models revealResearch square · 2026Article
- Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains.Cell stem cell · 2026Article
- Fibronectin mediates APOE4-driven blood-brain barrier dysfunction in Alzheimer's disease.Nature aging · 2026Article
- APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics.Nature communications · 2026Article
- Review
- APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice.Cell reports · 2026Article
- An ApoE-Associated Low-Inflammatory Microglial State Emerges After Inflammatory Challenge in Alzheimer's Disease Mice.Neuroscience bulletin · 2026Article
- GPR146 Deficiency Enhances Microglial Phagocytosis and Blood-Brain Barrier-Associated Markers in an Acute Amyloid-β Model.Molecular neurobiology · 2026Article
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- Astrocytic lipid dysregulation as an early driver of neurodegeneration.Nature reviews. Neurology · 2026Review
- From astrocyte cholesterol synthesis to synaptic dysfunction: mechanisms of neuron-glia lipid coupling.Molecular biology reports · 2026Review
- Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.Cell · 2026Review
- Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.Neuroscience bulletin · 2026Article
- Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate TransporterCurrent issues in molecular biology · 2026Article
- Article
201 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
21 authors at 7 institutions in 1 country.
Julia TcwDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: juliatcw@bu.edu.
Lu QianDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Nina H PipaliaDepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
Michael J ChaoDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Sanofi US, Cambridge, MA 02141, USA.
Shuang A LiangInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
Yang ShiDepartment of Neurology, Washington University School of Medicine, St. Louis, MO 63108, USA; Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA.
Bharat R JainInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
Sarah E BertelsenNash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Manav KapoorDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.
Edoardo MarcoraDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Elizabeth SikoraNash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Elizabeth J AndrewsDepartment of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, USA.
Alessandra C MartiniDepartment of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, USA.
Celeste M KarchHope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63108, USA.
Elizabeth HeadInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, USA.
David M HoltzmanDepartment of Neurology, Washington University School of Medicine, St. Louis, MO 63108, USA; Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA.
Bin ZhangDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Minghui WangDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Frederick R MaxfieldDepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
Wayne W PoonInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; NeuCyte, Inc., Mountain View, CA 94043, USA.
Alison M GoateDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: alison.goate@mssm.edu.
Icahn School of Medicine at Mount Sinai · USUniversity of California, Irvine · USWashington University in St. Louis · USBoston University · USCornell University · USRegeneron (United States) · USSanofi (United States) · US
Funding
Project 4 (Genetic modifiers for APOE-associated Alzheimer's disease pathogenesis)U19AG069701 · NIA · MAYO CLINIC JACKSONVILLE · PI Yingxue Ren · 2021 to 2026
$42.0MUC Irvine Alzheimer's Disease Research Center Induced Pluripotent Stem Cell CoreP50AG016573 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI LAFERLA, FRANK M · 2000 to 2019
$37.0MResearch Education ComponentP30AG066444 · NIA · WASHINGTON UNIVERSITY · PI DAVID M. HOLTZMAN · 2020 to 2026
$28.7MThe Alzheimer's Disease Research Center at the University of California, IrvineP30AG066519 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI Elizabeth Head · 2020 to 2026
$27.9MIntegrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's DiseaseU01AG046170 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI EHRLICH, MICHELLE E, GANDY, SAMUEL E. · 2013 to 2022
$26.0MMacrophage-Lipoprotein InteractionsR01HL093324 · NHLBI · WEILL MEDICAL COLL OF CORNELL UNIV · PI MAXFIELD, FREDERICK R. · 2009 to 2025
$6.7MEffect of APOE on CNS Neurons: Role of LRPRF1NS090934 · NINDS · WASHINGTON UNIVERSITY · PI HOLTZMAN, DAVID M. · 2020 to 2025
$6.5MGenomic approach to identification of microglial networks involved in Alzheimer’s disease riskU01AG058635 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI GOATE, ALISON M · 2018 to 2022
$4.8MMolecular Characterization and Validation of Gender Differences in Alzheimers Disease PathogenesisRF1AG054014 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI CAI, DONGMING, ZHANG, BIN · 2016 to 2016
$4.2MNovel Strategies and Mechanisms to Target APOE and Alzheimer's DiseaseRF1AG047644 · NIA · WASHINGTON UNIVERSITY · PI HOLTZMAN, DAVID M., HYMAN, BRADLEY T. · 2019 to 2019
$3.8MDissect the interplay between sex and APOE at the single cell level to uncover novel pathways, targets and therapeutics for Alzheimer's diseaseRF1AG074010 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI CAI, DONGMING, ZHANG, BIN · 2021 to 2021
$3.6MTowards a comprehensive signaling pathway map of parahippocampal vulnerability in Alzheimers DiseaseRF1AG057440 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI HAROUTUNIAN, VAHRAM, NOGGLE, SCOTT ALLEN · 2017 to 2017
$3.5MNCRR NIH HHS S10 RR025496NHLBI NIH HHS R01 HL093324NIA NIH HHS K01 AG062683NIA NIH HHS P30 AG066444NIA NIH HHS P30 AG066519NIA NIH HHS P50 AG016573NIA NIH HHS R01 AG068992NIA NIH HHS RF1 AG047644NIA NIH HHS RF1 AG054014NIA NIH HHS RF1 AG057440NIA NIH HHS RF1 AG068992NIA NIH HHS RF1 AG074010NIA NIH HHS U01 AG046170NIA NIH HHS U01 AG058635NIA NIH HHS U19 AG069701NIH HHS S10 OD010794NIH HHS S10 OD021718NINDS NIH HHS RF1 NS090934
Abstract
The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
Indexed as
Alzheimer DiseaseInduced Pluripotent Stem CellsAnimalsApolipoprotein E3Apolipoprotein E4Apolipoproteins EAstrocytesCholesterolHumansMiceMicrogliaApolipoprotein E3Apolipoprotein E4Apolipoproteins ECholesterolAlzheimerAPOEastrocytescholesterolgenetic heterogeneityhaplotypesinflammationiPSC disease modelingmatrisomemicroglia
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