ArticleNeuron2020
Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology.
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30citing papers in PubMed, 2 pooled it
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Who cites it
30 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Pooled it
- Genetic architecture of epigenetic cortical clock age in brain tissue from older individuals: alterations inEpigenetics · 2024Pooled it
- TMEM106B is a selective modulator of TDP-43 pathology in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Characterizing Individuals Fulfilling Clinical Criteria for Limbic-Predominant Age-Related TDP-43 Encephalopathy in a Tertiary Memory Clinic.Neurology · 2026Article
- Neurodegeneration risk variants promote lysosomal TMEM106B fibril accumulation.bioRxiv : the preprint server for biology · 2026Article
- Genetic variation in TMEM106B alters microglial activation and cytokine responses in chronic traumatic encephalopathy.Acta neuropathologica · 2025Article
- Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis.Journal of neuropathology and experimental neurology · 2024Review
- Physiological and pathological functions of TMEM106B in neurodegenerative diseases.Cellular and molecular life sciences : CMLS · 2024Review
- Association of TMEM106B with CorticalGenes · 2024Article
- Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures for asymptomatic and symptomatic Alzheimer's disease.Research square · 2024Article
- miR-129-5p as a biomarker for pathology and cognitive decline in Alzheimer's disease.Alzheimer's research & therapy · 2024Article
- TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models.iScience · 2023Article
- miR-129-5p as a biomarker for pathology and cognitive decline in Alzheimer's disease.Research square · 2023Article
- TMEM106B aggregation in neurodegenerative diseases: linking genetics to function.Molecular neurodegeneration · 2023Review
- Article
- When Alzheimer's is LATE: Why Does it Matter?Annals of neurology · 2023Review
- Limbic-Predominant Age-Related TDP-43 Encephalopathy: LATE-Breaking Updates in Clinicopathologic Features and Biomarkers.Current neurology and neuroscience reports · 2022Review
- Multiple gene variants linked to Alzheimer's-type clinical dementia via GWAS are also associated with non-Alzheimer's neuropathologic entities.Neurobiology of disease · 2022Article
- Bridging the splicing gap in human genetics with long-read RNA sequencing: finding the protein isoform drivers of disease.Human molecular genetics · 2022Review
- Neuroimmune contributions to Alzheimer's disease: a focus on human data.Molecular psychiatry · 2022Review
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Authors and funding
14 authors.
Hyun-Sik YangCenter for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Charles C WhiteThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA.
Hans-Ulrich KleinThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA.
Lei YuRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Christopher GaiteriRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Yiyi MaThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA.
Daniel FelskyThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA.
Sara MostafaviDepartment of Statistics, Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada; Canadian Institute for Advanced Research, Toronto, ON M5G 1M1, Canada.
Vladislav A PetyukPacific Northwest National Laboratory, Richland, WA 99354, USA.
Reisa A SperlingCenter for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
Nilüfer Ertekin-TanerDepartment of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Julie A SchneiderRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
David A BennettRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Philip L De JagerThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: pld2115@cumc.columbia.edu.
Funding
SUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BARNES, LISA L · 1991 to 2020
$49.1MEPIDEMIOLOGY OF NEURAL RESERVE AND NEUROBIOLOGY IN AGINGR01AG017917 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2001 to 2023
$43.3MIntegrating the exposome and methylome to inform brain molecular changes in ADRD across established diverse cohorts.U01AG046139 · NIA · UNIVERSITY OF FLORIDA · PI ERTEKIN-TANER, NILUFER, PETERS, METTE · 2013 to 2022
$24.6MRISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4MMulti-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targetsU01AG061356 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2018 to 2022
$13.7MPathway discovery, validation and compound identification for Alzheimer's disease - SupplementU01AG046152 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2013 to 2017
$13.6MIntegrative translational discovery of vascular risk factors in aging and dementiaRF1AG051504 · NIA · MAYO CLINIC JACKSONVILLE · PI BU, GUOJUN, ERTEKIN-TANER, NILUFER · 2015 to 2019
$9.8MCharacterizing TDP-43 related hippocampal degeneration and memory loss in agingR01AG067482 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI SCHNEIDER, JULIE A. · 2020 to 2024
$6.8MHarnessing Molecular Networks of Resilience for Therapeutic Discoveries in ADR01AG061796 · NIA · MAYO CLINIC JACKSONVILLE · PI ERTEKIN-TANER, NILUFER · 2018 to 2022
$5.7MIdentifying the molecular systems, networks, and key molecules that underlie cognitive resilienceR01AG057911 · NIA · UPSTATE MEDICAL UNIVERSITY · PI GAITERI, CHRISTOPHER A. · 2017 to 2021
$3.8MExploring the Role of the Brain Transcriptome in Cognitive DeclineR01AG036836 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI DE JAGER, PHILIP L · 2011 to 2014
$2.9MEpidemiologic Study of TDP-43 Pathology in Aging and DementiaR01AG042210 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI SCHNEIDER, JULIE A. · 2012 to 2018
$2.4MNIA NIH HHS K23 AG062750NIA NIH HHS P30 AG010161NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG036836NIA NIH HHS R01 AG042210NIA NIH HHS R01 AG057911NIA NIH HHS R01 AG061796NIA NIH HHS R01 AG067482NIA NIH HHS RF1 AG051504NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG061356
Abstract
Here, we perform a genome-wide screen for variants that regulate the expression of gene co-expression modules in the aging human brain; we discover and replicate such variants in the TMEM106B and RBFOX1 loci. The TMEM106B haplotype is known to influence the accumulation of TAR DNA-binding protein 43 kDa (TDP-43) proteinopathy, and the haplotype's large-scale transcriptomic effects include the dysregulation of lysosomal genes and alterations in synaptic gene splicing that are also seen in the pathophysiology of TDP-43 proteinopathy. Further, a variant near GRN, another TDP-43 proteinopathy susceptibility gene, shows concordant effects with the TMEM106B haplotype. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE-amyloid-β effects converge to alter myelination and lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk haplotype and uncover a transcriptional program that mediates the converging effects of APOE-amyloid-β and TMEM106B on TDP-43 aggregation in older adults.
Indexed as
AgedAged, 80 and overAgingAlzheimer DiseaseAmyloid beta-PeptidesApolipoproteins EBrainCohort StudiesDNA-Binding ProteinsFemaleGene Expression RegulationHaplotypesHumansLysosomesMaleMembrane ProteinsAmyloid beta-PeptidesApolipoproteins EDNA-Binding ProteinsGRN protein, humanMembrane ProteinsNerve Tissue ProteinsProgranulinsRBFOX1 protein, humanRNA Splicing FactorsTARDBP protein, humanTMEM106B protein, humanAlzheimer's diseaseAmyloid-βco-expression modulecognitive resilienceeQTLexpression quantitative trait lociGRNRBFOX1splicing quantitative trait locisQTLTDP-43TMEM106B
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