ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways.
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Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8citing papers in PubMed
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Who cites it
8 citing papers in PubMed.
- Understanding Neurodegenerative Diseases From the -Omics Perspective: Lessons Learnt.Annals of neurology · 2026Review
- PRISM-xQTL: Pleiotropic Relationships Integrated with System-level Multiomic QTL analysis for causal genes and molecular mediators in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- RBFOX1 association with age at onset of Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Alzheimer Syndrome or Age-Related Dementia-History, Therapy and Prevention.Journal of clinical medicine · 2025Article
- Chromosome 12 and Environmental Factors in Parkinson's Disease: An All of Us Data Analysis.Genes · 2025Article
- Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer's Disease.PLoS genetics · 2025Article
- Inhibition of brain glutamate carboxypeptidase II (GCPII) to enhance cognitive function.Advances in pharmacology (San Diego, Calif.) · 2025Review
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Authors and funding
28 authors.
Joseph BradleyNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Cyril PottierNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Eder Lucio da FonsecaThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
Jiji Thulaseedhara KurupTaub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA.
Daniel WesternNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Ciyang WangNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Achal NeupaneNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Nicholas R RayTaub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA.
Melissa Jean-FrancoisThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
Muhammad AliNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Jigyasha TimsinaNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Kristy BergmannNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
John BuddeNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Eden R MartinThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
Margaret A Pericak-VanceThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
Michael CuccaroThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
Adam C NajDepartment of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Brian W KunkleThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
Alzheimer's Disease Genetics Consortium (ADGC), Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight‐ADRC)
Gerard D SchellenbergPenn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Victoria FernandezNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Jonathan HainesDepartment of Population & Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
John C MorrisDepartment of Neurology, Washington University School in St. Louis, St. Louis, Missouri, USA.
David M HoltzmanDepartment of Neurology, Washington University School in St. Louis, St. Louis, Missouri, USA.
Richard J PerrinDepartment of Pathology and Immunology, Washington University in St. Louis, St. Louis, Missouri, USA.
Christiane ReitzTaub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA.
Gary W BeechamThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
Carlos CruchagaNeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.ORCID 0000-0002-0276-2899
Funding
Alzheimer's Disease Neuroimaging Initiative - SupplementU01AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE RES &EDUC · PI WEINER, MICHAEL W · 2004 to 2015
$121.0MNational Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8MTRIAL OF VALPROATE TO ATTENUATE THE PROGRESSION OF ADU01AG010483 · NIA · UNIVERSITY OF ROCHESTER · PI AISEN, PAUL S. · 1991 to 2012
$116.2MVascular Structure and Function in Cognitive AgingP01AG003949 · NIA · YESHIVA UNIVERSITY · PI Richard B. LIPTON · 1985 to 2026
$73.9MSmartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI JOHN MORRIS · 1985 to 2026
$69.5MTDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2MAlzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4MTHERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI GRABOWSKI, THOMAS J. · 1985 to 2019
$57.2MVIRUS-INDUCED BRAIN PATHOLOGYP50AG005131 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GALASKO, DOUGLAS R · 1985 to 2018
$55.4MWASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 1985 to 2019
$52.1MSUPPLEMENT TO ALZHEIMERS DISEASE PATIENT REGISTRYU01AG006786 · NIA · MAYO CLINIC ROCHESTER · PI GRAFF-RADFORD, JONATHAN, JACK, CLIFFORD R. · 1986 to 2023
$49.6MThe natural history of AB accumulation in preclinical ADP01AG026276 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 2005 to 2025
$49.5MAbbVieAccelerating Medicines Partnership (AMP-AD) P30AG10161Accelerating Medicines Partnership (AMP-AD) P30AG19610Accelerating Medicines Partnership (AMP-AD) P30AG72975Accelerating Medicines Partnership (AMP-AD) P50AG016574Accelerating Medicines Partnership (AMP-AD) R01AG003949Accelerating Medicines Partnership (AMP-AD) R01AG017216Accelerating Medicines Partnership (AMP-AD) R01AG018023Accelerating Medicines Partnership (AMP-AD) R01AG025711Accelerating Medicines Partnership (AMP-AD) R01AG032990Accelerating Medicines Partnership (AMP-AD) R01AG036836Accelerating Medicines Partnership (AMP-AD) R01AG15819Accelerating Medicines Partnership (AMP-AD) R01AG17917Accelerating Medicines Partnership (AMP-AD) R01NS080820Accelerating Medicines Partnership (AMP-AD) RF1AG057440Accelerating Medicines Partnership (AMP-AD) U01AG006576Accelerating Medicines Partnership (AMP-AD) U01AG006786Accelerating Medicines Partnership (AMP-AD) U01AG046139Accelerating Medicines Partnership (AMP-AD) U01AG046170Accelerating Medicines Partnership (AMP-AD) U01AG46152Accelerating Medicines Partnership (AMP-AD) U01AG61356Accelerating Medicines Partnership (AMP-AD) U24AG061340Accelerating Medicines Partnership (AMP-AD) U24NS072026Alzheimer's AssociationAlzheimer's Association Zenith Fellows Award ZEN-22-848604Alzheimer's Disease Cooperative StudyAlzheimer's Drug Discovery FoundationAraclon BiotechArizona Department of Health Services and the Arizona Biomedical Research CommissionBin ZhangBiomedical Laboratory Research ProgramBoston University R01AG33193Boston University U01 AG10483BRACEBrain Net EuropeBrightFocus Foundation A2111048CereSpir, Inc.Chan Zuckerberg InitiativeCure PSPDavid Bennett, Christopher GaiteriDepartment of Defense W81XWH-12-2-0012Departments of Neurology and Psychiatry at Washington University School of MedicineDuke University AG05128Eisai Inc.Elan Pharmaceuticals, Inc.Emory University AG025688Eric SchadtEuroImmunGE HealthcareGenotype-Tissue Expression (GTExGlaxo Smith Kline IIRG-05-14147Glaxo Smith Kline IIRG-08-89720Group Health Research Institute UO1 AG006781Group Health Research Institute UO1 HG004610Group Health Research Institute UO1 HG006375Hersenstichting Nederland Breinbrekend WerkHigher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART)Howard Hughes Medical InstituteIndiana University P30 AG10133Institut de NeuropatologiaInternationale Stiching Alzheimer OnderzoekInternational Parkinson FondsIXICO Ltd.Janssen Alzheimer Immunotherapy Research & Development, LLC.Johnnie B. Byrd Sr. Alzheimer's InstituteJohnson & Johnson Pharmaceutical Research & Development LLC.Kathleen Price Bryan Brain Bank at Duke University Medical CenterKoichi IijimaKronos Science AG041232Laboratory for Neuro Imaging at the University of Southern California P01AG026276Laboratory for Neuro Imaging at the University of Southern California P01AG03991Laboratory for Neuro Imaging at the University of Southern California P30AG066444Lara Mangravitelocal NHS trusts and Newcastle UniversityLondon Brain Bank for Neurodegenerative DiseasesLumosityMayo and Michael J Fox foundationsMayo Clinic Brain BankMedical Research CouncilMeso Scale Diagnostics, LLC.Michael J. Fox FoundationMichelle EhrlichMount Sinai/JJ Peters VA Medical Center NIH Brain and Tissue RepositoryNathan PriceNational Cell Repository for Alzheimer's Disease U24 AG21886National Center for Geriatrics and Gerontology, JapanNational Institute on Aging Alzheimer's Disease Data Storage SiteNCI NIH HHS R01 CA129769NCRR NIH HHS KL2 RR024151NCRR NIH HHS UL1 RR029893Netherlands Brain BankNeuroGenomics and Informatics CenterNeuroRx ResearchNeurotrack TechnologiesNewcastle Brain Tissue ResourceNew York University 1R01AG035137New York University 1RC2AG036502New York University 5R01AG012101New York University 5R01AG013616New York University 5R01AG022374New York University P30 AG08051NHGRI NIH HHS U01 HG004610NHGRI NIH HHS U01 HG006375NHGRI NIH HHS U01 HG008657NIA NIH HHS AG052410NIA NIH HHS P01 AG002219NIA NIH HHS P01 AG003949NIA NIH HHS P01 AG003991NIA NIH HHS P01 AG010491NIA NIH HHS P01 AG017216NIA NIH HHS P01 AG019724NIA NIH HHS P01 AG026276NIA NIH HHS P30 AG008017NIA NIH HHS P30 AG008051NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG010129NIA NIH HHS P30 AG010133NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG012300NIA NIH HHS P30 AG013846NIA NIH HHS P30 AG013854NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG028377NIA NIH HHS P30 AG028383NIA NIH HHS P30 AG066444NIA NIH HHS P30 AG066515NIA NIH HHS P30 AG066518NIA NIH HHS P30 AG072947NIA NIH HHS P30 AG072975NIA NIH HHS P50 AG005128NIA NIH HHS P50 AG005131NIA NIH HHS P50 AG005133NIA NIH HHS P50 AG005134NIA NIH HHS P50 AG005136NIA NIH HHS P50 AG005138NIA NIH HHS P50 AG005142NIA NIH HHS P50 AG005144NIA NIH HHS P50 AG005146NIA NIH HHS P50 AG005681NIA NIH HHS P50 AG008671NIA NIH HHS P50 AG008702NIA NIH HHS P50 AG016570NIA NIH HHS P50 AG016573NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG016582NIA NIH HHS P50 AG023501NIA NIH HHS P50 AG025688NIA NIH HHS P50 AG025711NIA NIH HHS P50 AG033514NIA NIH HHS R00 AG062723NIA NIH HHS R01 AG009029NIA NIH HHS R01 AG009956NIA NIH HHS R01 AG012101NIA NIH HHS R01 AG013616NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017173NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG018023NIA NIH HHS R01 AG019085NIA NIH HHS R01 AG019757NIA NIH HHS R01 AG020688NIA NIH HHS R01 AG021547NIA NIH HHS R01 AG022018NIA NIH HHS R01 AG022374NIA NIH HHS R01 AG025259NIA NIH HHS R01 AG026390NIA NIH HHS R01 AG026916NIA NIH HHS R01 AG027944NIA NIH HHS R01 AG028786NIA NIH HHS R01 AG030146NIA NIH HHS R01 AG030653NIA NIH HHS R01 AG031581NIA NIH HHS R01 AG032990NIA NIH HHS R01 AG033193NIA NIH HHS R01 AG035137NIA NIH HHS R01 AG036836NIA NIH HHS R01 AG037212NIA NIH HHS R01 AG041232NIA NIH HHS R01 AG041718NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG042437NIA NIH HHS R01 AG044546NIA NIH HHS R01 AG048927NIA NIH HHS R37 AG015473NIA NIH HHS RC2 AG036502NIA NIH HHS RC2 AG036528NIA NIH HHS RC2 AG036650NIA NIH HHS RF1 AG053303NIA NIH HHS RF1 AG057440NIA NIH HHS RF1 AG058501NIA NIH HHS RF1 AG074007NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG006786NIA NIH HHS U01 AG010483NIA NIH HHS U01 AG024904NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG046170NIA NIH HHS U01 AG052410NIA NIH HHS U01 AG058922NIA NIH HHS U01 AG061356NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG026395NIA NIH HHS U24 AG041689NIA NIH HHS U24 AG061340NIA NIH HHS U24 AG072122NIA NIH HHS U54 AG052427NIBIB NIH HHSNIH HHS P01AG003991NIH HHS P30 AG066515NIH HHS R00AG062723NIH HHS R01AG044546NIH HHS RF1AG053303NIH HHS RF1AG058501NIH HHS RF1AG074007NIH HHS U01AG058922Nilüfer Ertekin-TanerNIMHD NIH HHS P20 MD000546NIMH NIH HHS P50 MH060451NIMH NIH HHS R01 MH080295NINDS NIH HHS P50 NS039764NINDS NIH HHS R01 NS059873NINDS NIH HHS R01 NS080820NINDS NIH HHS U24 NS072026North Bristol NHS Trust Research and Innovation Department and DeNDRoNNorth Carolina A&T University R01 AG28786-01A1Northern California Institute for Research and EducationOffice of Research and DevelopmentPhilip De JagerPiramal ImagingRush University R01 AG01101Rush University R01 AG15819Rush University R01 AG17917Rush University R01 AG22018Sam GandyScott NoggleServei Anatomia PatologicaServierSouth West Dementia Brain BankSteven YounkinStichting MS ResearchSun Health Research Institute Brain and Body Donation ProgramTakeda Pharmaceutical CompanyThe Banner Alzheimer's Foundationthe Canadian Institute of Health Researchthe Hope Center for Neurological DisordersTodd GoldeTransition TherapeuticsUniversitat de BarcelonaUniversity of Kentucky AG05144University of Miami AG010491University of Miami AG019757University of Miami AG021547University of Miami AG027944University of Pennsylvania R01AG041797University of Pennsylvania U24 AG026390University of Pennsylvania U24-AG041689University of Pittsburgh AG02365University of Pittsburgh AG030653University of Pittsburgh AG041718University of Pittsburgh AG07562University of Washington P50AG005136University of Washington R01AG042437University of Wisconsin P50AG033514US Department of Veterans Affairs AdministrationVahram HaroutunianVanderbilt University R01AG019085Washington University P01AG026276Washington University P01AG03991Washington University P50AG005681Wellcome Trust
Abstract
introductionMost genetic studies for Alzheimer's disease (AD) have been focused on late-onset AD (LOAD). There are no large genetic studies on early-onset AD (EOAD).
methodsWe performed a multi-ancestry (non-Hispanic European, African, and East Asian) genome-wide association study (GWAS) including a total of 7,349 cases and 17,887 control. Cases with age at onset younger than 70 years were included. Sensitivity analysis including cases with onset <65 was performed. Only controls older than 70 were included to decrease the risk of developing LOAD.
resultsWe identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and functional annotations, we nominate eight novel genes that are involved in microglia activation, glutamate production, and signaling pathways. DISCUSSION: EOAD, although sharing genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification. HIGHLIGHTS: We performed the largest and first multi-ethnic genetic screening for early-onset Alzheimer's disease (AD). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. The novel genes are implicated microglia activation, glutamate production, and signaling pathways. EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.
Indexed as
Alzheimer DiseaseGenetic Predisposition to DiseaseGlutamic AcidSignal TransductionAgedAge of OnsetFemaleGenome-Wide Association StudyHumansMaleMiddle AgedPolymorphism, Single NucleotideQuantitative Trait LociGlutamic AcidADGCAlzheimer's disease riskearly onset Alzheimer's diseasegene‐mappinggenetic ancestryGWASlate onset Alzheimer's diseasemeta‐analysismulti‐ancestry
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