ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2026
APOE and genetic risk variants influence Alzheimer's disease onset in carriers of an extra copy of APP, with and without Down syndrome.
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- APOE and genetic risk variants influence Alzheimer's disease onset in carriers of an extra copy of APP, with and without Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
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Authors and funding
40 authors.
Joan GroeneveldGenomics of Neurodegenerative Diseases and Aging, Human Genetics, Amsterdam UMC location VUmc, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Danna PerlazaSant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Clàudia OlivéAce Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain.
Lou GrangeonInserm U1245 and, Department of Neurology and CNRMAJ, Univ Rouen Normandie, Normandie Univ, CHU Rouen, Rouen, France.
Niccolo TesiGenomics of Neurodegenerative Diseases and Aging, Human Genetics, Amsterdam UMC location VUmc, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Aude NicolasInserm, U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Univ. Lille, CHU Lille, Institut Pasteur de Lille, Lille, France.
Chenyang JiangAlzheimer Center Amsterdam, Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Itziar de RojasNetwork Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
David WallonInserm U1245 and, Department of Neurology and CNRMAJ, Univ Rouen Normandie, Normandie Univ, CHU Rouen, Rouen, France.
Stéphane RousseauUniv Rouen Normandie, Normandie Univ, CHU Rouen, Inserm U1245 and Department of Genetics and CNRMAJ, Rouen, France.
Marta RoviraAce Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain.
Diego Real de AsúaAdult Down Syndrome Unit, Department of Internal Medicine, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa, Madrid, Spain.
Fernando MoldenhauerAdult Down Syndrome Unit, Department of Internal Medicine, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa, Madrid, Spain.
Ruihao MuInstituto de Investigación Sanitaria Hospital Universitario de La Princesa, Madrid, Spain.
Kévin CassinariInserm U1245 and, Department of Neurology and CNRMAJ, Univ Rouen Normandie, Normandie Univ, CHU Rouen, Rouen, France.
Aline ZareaInserm U1245 and, Department of Neurology and CNRMAJ, Univ Rouen Normandie, Normandie Univ, CHU Rouen, Rouen, France.
Joaquim Aumatell EscabiasSant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Jean-Charles LambertInserm, U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Univ. Lille, CHU Lille, Institut Pasteur de Lille, Lille, France.
Yolande A L PijnenburgAlzheimer Center Amsterdam, Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Marc HulsmanGenomics of Neurodegenerative Diseases and Aging, Human Genetics, Amsterdam UMC location VUmc, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Everard G B VijverbergAlzheimer Center Amsterdam, Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Johannes LevinDepartment of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
Mathias JuckerGerman Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Eric McDadeDepartment of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Juan ForteaSant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Henne HolstegeGenomics of Neurodegenerative Diseases and Aging, Human Genetics, Amsterdam UMC location VUmc, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Flora H DuitsAlzheimer Center Amsterdam, Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Lisa VermuntAlzheimer Center Amsterdam, Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Maulikkumar PatelDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
Matthew JohnsonDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
Alan E RentonRonald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Alison M GoateDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
Carlos CruchagaDepartment of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Cyril PottierDepartment of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Maria Victoria FernandezAce Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain.
Olivia BelbinSant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Gael NicolasUniv Rouen Normandie, Normandie Univ, CHU Rouen, Inserm U1245 and Department of Genetics and CNRMAJ, Rouen, France.
Oriol Dols-IcardoSant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Sven J van der LeeGenomics of Neurodegenerative Diseases and Aging, Human Genetics, Amsterdam UMC location VUmc, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Dominantly Inherited Alzheimer Network
Funding
Imaging CoreU19AG032438 · NIA · WASHINGTON UNIVERSITY · PI BATEMAN, RANDALL J · 2010 to 2025
$53.9MDS-ARC: A Remote Digital Cognitive Assessment for Down Syndrome-Associated Alzheimer's DiseaseR01AG081394 · NIA · WASHINGTON UNIVERSITY · PI Jason J Hassenstab · 2023 to 2026
$6.0MThe Role of Inflammation and NGF Dysfunction in the Evolution of Alzheimer Disease Pathology in Down Syndrome-RevisionRF1AG056850 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI BUSCIGLIO, JORGE A, CUELLO, A CLAUDIO · 2018 to 2020
$5.9MClinical trials to prevent Alzheimer's Disease in Down SyndromeR61AG066543 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI RAFII, MICHAEL S · 2019 to 2020
$5.6MTau pathology in Down syndrome and Alzheimer'sRF1AG061566 · NIA · UNIVERSITY OF DENVER (COLORADO SEMINARY) · PI GRANHOLM-BENTLEY, ANN-CHARLOTTE ESTHER, MARGITTAI, MARTIN · 2019 to 2019
$3.4MBiological Correlates of Alzheimer in Down Syndrome.R21AG056974 · NIA · UNIVERSITY OF DENVER (COLORADO SEMINARY) · PI GRANHOLM-BENTLEY, ANN-CHARLOTTE ESTHER · 2017 to 2018
$414kAce Alzheimer Center Barcelona is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO)Alzheimer's Association AARF-22-924456Alzheimer's Association SG-20-690363-DIANCentro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII) CB06/05/2004Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII) CB18/05/00010Department de Salut de la Generalitat de Catalunya SLT006/17/00119Dutch Research Council 15318Dutch Research Council 17232Fondo de Investigaciones SanitarioFondo Europeo de Desarrollo Regional, Unión Europea, "Una manera de hacer Europa.Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer EuropaFundación bancaria "La Caixa," Fundación ADEY, Fundación Echevarne and Grífols SA (GR@ACE project)Fundación Tatiana Pérez de Guzmán el Bueno IIBSP-DOW-2020151German Center for Neurodegenerative DiseasesGerman Research FoundationHealth∼Holland, Topsector Life Sciences & Health #LSHM20106Horizon2020-Research and Innovation Framework Programme from the European Union H2020-SC1-BHC-2018-2020Institute of Health Carlos III FI20/00215Institute of Health Carlos III FI24/00029Institute of Health Carlos III INT21/00073Institute of Health Carlos III P22/I01403Institute of Health Carlos III PI19/01240Institute of Health Carlos III PI19/01301Institute of Health Carlos III PI20/01473Institute of Health Carlos III PI21/01395Institute of Health Carlos III PI23/01786Institute of Health Carlos III PI24/01087Institute on Aging U19AG032438Jerome Lejeune Foundation PDC-2023-51Korea Health Industry Development Institute (KHIDI), Korea Dementia Research Center (KDRC)Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea RS-2024-00344521National Institutes of Health grants 1R01AG056850-01A1National Institutes of Health grants 1R01AG081394-01National Institutes of Health grants 1R61AG066543-01National Institutes of Health grants R01AG061566National Institutes of Health grants R21AG056974Nederlandse Organisatie voor Wetenschappelijk Onderzoek #733050512NIA NIH HHS R01 AG081394NIA NIH HHS R21 AG056974NIA NIH HHS R61 AG066543NIA NIH HHS RF1 AG056850NIA NIH HHS RF1 AG061566NIA NIH HHS U19 AG032438Pascual Maragall Researchers Program 2023-1334PREADAPT Joint Program for Neurodegenerative Diseases (JPND) AC19/00097Raul Carrea Institute for Neurological Research (FLENI)Research and DevelopmentResearch and Development Grants for Dementia from Japan Agency for Medical Research and Development (AMED)Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum AmsterdamStichting DioraphteSURF CooperativeZonMw 1051003212000ZonMw #73305095007
Abstract
introductionAn extra copy of the amyloid precursor protein (APP) gene causes autosomal dominant Alzheimer's disease (AD) and AD in Down syndrome (DS), but the factors underlying variability in age at onset (AAO) remain unclear. We investigated whether sporadic AD risk variants modify AAO.
methodsWe analyzed clinical and genetic data from 100 APP duplication (APPdup) carriers and 957 individuals with DS. Cox models assessed associations of apolipoprotein E (APOE) ε2 and ε4 and the AD genetic risk score (AD-GRS; excluding APOE and chromosome 21 variants) with AAO.
resultsMean AAO was earlier in APPdup than DS (51 ± 7 vs. 53 ± 6 years; P = 0.0005). APOE ε2 delayed onset (hazard ratio [HR] = 0.47, P < 0.0001), whereas APOE ε4 (HR = 1.5, P = 0.0003) and higher AD-GRS (HR = 1.3 per standard deviation, P < 0.0001) accelerated onset. Predicted median AAO differed by 10 years between lowest and highest genetic risk. DISCUSSION: Sporadic AD genetic risk factors are important modifiers of AAO in APPdup and DS, explaining part of the marked variability in onset.
Indexed as
Alzheimer DiseaseAmyloid beta-Protein PrecursorApolipoproteins EDown SyndromeGenetic Predisposition to DiseaseAge of OnsetApolipoprotein E4FemaleGenetic Risk ScoreHeterozygoteHumansMaleMiddle AgedRisk FactorsAmyloid beta-Protein PrecursorApolipoprotein E4Apolipoproteins EAPP protein, humanAlzheimer's diseaseamyloid precursor protein duplicationapolipoprotein Eautosomal dominant Alzheimer's diseasedisease onsetDown syndromeDown syndrome‐associated Alzheimer's diseasepolygenic risk score
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