biostudies-literatureBradley JOffice of Research and DevelopmentVahram HaroutunianEmory UniversityNational Institutes of HealthAlzheimer&apos;s Associationthe Canadian Institute of Health ResearchNational Institute on AgingWashington UniversityInternational Parkinson FondsDuke UniversityUniversity of California, San DiegoNorth Bristol NHS Trust Research and Innovation Department and DeNDRoNMeso Scale Diagnostics, LLC.Araclon BiotechUS Department of Veterans Affairs AdministrationAlzheimer's AssociationCure PSPNIH HHSScott NoggleAlzheimer's Disease Cooperative StudyNorth Carolina A&T UniversityChan Zuckerberg InitiativeBoston UniversityNetherlands Brain BankLara MangraviteNational Cell Repository for Alzheimer's DiseaseVanderbilt UniversityWellcome TrustUniversity of MichiganPhilip De JagerInternationale Stiching Alzheimer OnderzoekUniversity of PennsylvaniaIXICO Ltd.University of California, San FranciscoEisai Inc.Laboratory for Neuro Imaging at the University of Southern CaliforniaServei Anatomia PatologicaTransition TherapeuticsGlaxo Smith KlineAlzheimer&apos;s Drug Discovery FoundationUniversity of California, Irvinelocal NHS trusts and Newcastle UniversitySouth West Dementia Brain BankUniversity of California, Los AngelesNational Institute of Biomedical Imaging and BioengineeringIndiana UniversityNCRR NIH HHSUniversity of ArizonaNeurotrack TechnologiesUniversity of Southern CaliforniaAbbVieKoichi IijimaNational Center for Geriatrics and Gerontology, JapanLondon Brain Bank for Neurodegenerative DiseasesMayo Clinic Brain BankNewcastle Brain Tissue ResourceJohnson & Johnson Pharmaceutical Research & Development LLC.University of WashingtonU.S. Department of DefenseAccelerating Medicines Partnership (AMP-AD)NHGRI NIH HHSNilüfer Ertekin-TanerSteven YounkinTodd GoldeLumosityJohns Hopkins UniversityNIA NIH HHSOregon Health and Science UniversityAlzheimer's Drug Discovery FoundationNIMH NIH HHSUniversity of KentuckyNorthwestern UniversityRush UniversityHigher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART)Stichting MS ResearchSam GandyUniversity of WisconsinUniversity of PittsburghEuroImmunUniversity of Alabama at BirminghamNorthern California Institute for Research and EducationNINDS NIH HHSSun Health Research Institute Brain and Body Donation ProgramServierNeuroGenomics and Informatics CenterMichelle EhrlichNational Institute on Aging Alzheimer's Disease Data Storage SiteAlzheimer's Association Zenith Fellows AwardJanssen Alzheimer Immunotherapy Research & Development, LLC.Elan Pharmaceuticals, Inc.Mount Sinai/JJ Peters VA Medical Center NIH Brain and Tissue RepositoryArizona Department of Health Services and the Arizona Biomedical Research CommissionDepartment of DefenseUniversity of MiamiNathan PriceMassachusetts General HospitalInstitut de NeuropatologiaColumbia UniversityMedical Research CouncilGenotype-Tissue Expression (GTExNew York UniversityMichael J. Fox Foundation for Parkinson&apos;s ResearchNIBIB NIH HHSHersenstichting Nederland Breinbrekend WerkHoward Hughes Medical InstituteKronos ScienceMayo ClinicBrightFocus FoundationGE HealthcareBiomedical Laboratory Research ProgramCereSpir, Inc.Takeda Pharmaceutical CompanyBrain Net EuropeKathleen Price Bryan Brain Bank at Duke University Medical CenterEric SchadtGroup Health Research InstituteUniversitat de BarcelonaBRACEDavid Bennett, Christopher GaiteriThe Banner Alzheimer's FoundationDepartments of Neurology and Psychiatry at Washington University School of MedicineMayo and Michael J Fox foundationsUniversity of California, Davisthe Hope Center for Neurological DisordersPiramal ImagingNeuroRx ResearchMichael J. Fox FoundationNIMHD NIH HHSJohnnie B. Byrd Sr. Alzheimer's InstituteNCI NIH HHSBin Zhange70377https://www.ebi.ac.uk/biostudies/studies/S-EPMC12187977biostudies-literatureUnknown21(6)<h4>Introduction</h4>Most 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).<h4>Methods</h4>We 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.<h4>Results</h4>We 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 quantiAlzheimer's & dementia : the journal of the Alzheimer's AssociationNovel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways.PMC12187977ZEN-22-848604IIRG-05-14147RF1AG058501R01 AG01101U24 AG026395R01 AG009956AG041232UO1 HG004610R01 AG019085R37 AG015473U24 AG026390U24AG061340P30 AG066444P30 AG019610R01 AG022018R01 AG048927U01 AG046170U01 AG10483R01 AG027944KL2 RR024151R00AG062723R01 AG022374R01 AG030146P30 AG010124P30 AG012300U01AG046170R01 AG17917R01 AG017173R01 AG018023RF1 AG058501R01 AG037212RF1 AG053303R01AG003949R01 AG019757R01 AG042437P50 MH060451RC2 AG036502U01 AG032984U24-AG041689P50 NS039764U24 AG041689P01 AG003991U01AG006786R01AG041797UO1 HG006375AG027944R01AG044546P30 AG010133R01 AG036836P01 AG019724P50 AG005681R01 AG012101P50AG033514P50 AG008671R01 AG032990P30AG10161U24 AG021886U24 NS072026P01 AG002219R01 AG044546U01 AG046152R01 AG026916RF1AG074007R01NS080820R01 AG041797R01AG025711R01AG036836P30 AG008051R01 MH080295P30 AG010129P50 AG016582P50 AG025688RF1AG053303P01AG03991R01 AG041718U24 AG061340R01AG032990P50 AG016574U01AG46152R01 AG025259P50 AG016573R01 AG017917R01AG17917P50 AG016570U01AG058922UL1 RR029893R01 AG013616P30 AG10133P30 AG08051P50 AG0051465R01AG012101P50 AG025711RF1 AG057440P01 AG010491AG021547P50 AG005142P30 AG066515U01 AG046139P50 AG005144P01AG026276U24NS072026UO1 AG006781R01AG019085U01AG046139AG041718U01 AG058922AG030653R00 AG062723R01AG042437U24 AG21886U54 AG052427P50 AG008702RF1AG057440R01 AG15819P30 AG0101615R01AG022374U01 HG006375P01 AG003949U24‐AG041689U24 AG072122R01 NS080820IIRG-08-89720AG05144R01 AG28786-01A1P50AG005136U01 AG052410R01 AG028786AG07562R01 AG015819U01 AG061356P30 AG013846P30 AG028383W81XWH‐12‐2‐0012AG025688P50 AG005128P30AG19610U01 AG010483P30 AG008017R01 AG030653U01AG61356P50AG005681P50 AG033514R01 AG026390U01 AG006786R01 AG031581R01 CA129769W81XWH-12-2-0012U01 AG0067815R01AG013616R01 AG021547P30 AG072975P50AG016574AG023651RC2AG036502P50 AG023501AG019757RC2 AG0366501R01AG035137R01 AG22018A2111048P30 AG013854R01 AG041232P50 AG005138P30AG72975R01AG017216U01AG006576R01 AG009029P50 AG005134U01 HG004610P30 AG028377P50 AG005136R01 NS059873R01AG018023RF1 AG074007P50 AG005131R01AG33193P01 AG017216P50 AG005133R01 AG035137R01 AG020688RC2 AG036528R01 AG033193AG05128P01AG003991P20 MD000546P30AG066444P01 AG026276U01 HG008657U01 AG024904AG010491AG052410R01AG15819Wang CMartin ERReitz CNaj ACSchellenberg GDBudde JCuccaro MPericak-Vance MANeupane AFernandez VKurup JTPerrin RJRay NRTimsina JAlzheimer's Disease Genetics Consortium (ADGC), Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight‐ADRC)Jean-Francois Mda Fonseca ELHoltzman DMWestern DAli MHaines JMorris JCKunkle BWCruchaga CBeecham GWBergmann KBradley JPottier CfalseNovel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways.<h4>Introduction</h4>Most 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).<h4>Methods</h4>We 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.<h4>Results</h4>We 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 quanti2025-01-01T00:00:00Z2025 Jun2026-06-03T07:27:35.894Z2026-04-25T03:22:33.972ZS-EPMC121879774055631810.1002/alz.70377