{
  "abstract": "Among the more than 90 identified genetic risk loci for late-onset Alzheimer’s disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1–10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11–13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases. Genome-wide association analyses of Alzheimer’s disease stratified by APOE carrier status identify variants whose effects are attenuated or augmented by the ε4 risk allele.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark. jesper.qvist.thomassen@regionh.dk",
    "Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA",
    "Nuffield Department of Population Health, University of Oxford, Oxford, UK",
    "Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France",
    "Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland",
    "Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain",
    "Network Center on Biomedical Research in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, Madrid, Spain",
    "PhD Program in Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain",
    "UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK",
    "Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan",
    "BK FOUR Department of Integrative Biological Sciences, Chosun University, Gwangju, Republic of Korea",
    "Department of Biomedical Science, Chosun University, Gwangju, Republic of Korea",
    "Gwangju Alzheimer's & Related Dementia (GARD) Cohort Research Center, Chosun University, Gwangju, Republic of Korea",
    "Well-aging Medicare Institute & CSU G-LAMP Project Group, Chosun University, Gwangju, Republic of Korea",
    "Division of Life Science, State Key Laboratory of Molecular Neuroscience and Daniel and Mayce Yu Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China",
    "Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong, China",
    "Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium",
    "VIB Center for Molecular Neurology, VIB, Antwerp, Belgium",
    "Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg",
    "Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain",
    "Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo, Spain",
    "Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy",
    "Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy",
    "Norwegian National Centre for Aging and Health, Vestfold Health Trust, Tønsberg, Norway",
    "The Research Centre for Age-related Functional Decline and Disease, Innlandet Hospital Trust, Ottestad, Norway",
    "Coalition for Aligning Science, Chevy Chase, MD, USA",
    "Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy",
    "Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy",
    "Laboratory of Experimental Neuropsychobiology, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Rome, Italy",
    "Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain",
    "Instituto de Investigacion Sanitaria 'Hospital la Paz' (IdIPaz), Madrid, Spain",
    "Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy",
    "Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy",
    "Fundación Pública Galega de Medicina Xenómica-IDIS, Santiago de Compostela, Spain",
    "Grupo de Medicina Xenómica, CIBERER, CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain",
    "Faculty of Medicine, University of Lisbon, Lisbon, Portugal",
    "Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany",
    "German Center for Neurodegenerative Diseases (DZNE), Munich, Germany",
    "Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany",
    "Munich Cluster for Systems Neurology (SyNergy), Munich, Germany"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 100,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jesper Qvist Thomassen",
      "orcid": "0000-0003-3484-9531"
    },
    {
      "affs": [
        1
      ],
      "name": "Hampton Leonard",
      "orcid": "0000-0003-2390-8110"
    },
    {
      "affs": [
        2
      ],
      "name": "Brittany Ulms"
    },
    {
      "affs": [
        3
      ],
      "name": "Benjamin Grenier‐Boley",
      "orcid": "0009-0004-3412-3997"
    },
    {
      "affs": [
        4
      ],
      "name": "Sami Heikkinen",
      "orcid": "0000-0002-6083-2402"
    },
    {
      "affs": [
        5,
        6,
        7
      ],
      "name": "Pablo García‐González",
      "orcid": "0000-0003-0125-5403"
    },
    {
      "affs": [
        8
      ],
      "name": "Atahualapa Castillo-Morales"
    },
    {
      "affs": [
        9
      ],
      "name": "Masataka Kikuchi",
      "orcid": "0000-0002-9562-841X"
    },
    {
      "affs": [
        10,
        11,
        12,
        13
      ],
      "name": "Jungsoo Gim",
      "orcid": "0000-0002-6454-9751"
    },
    {
      "affs": [
        14,
        15
      ],
      "name": "Han Cao",
      "orcid": "0000-0001-9992-9108"
    },
    {
      "affs": [
        16,
        17
      ],
      "name": "Fahri Küçükali",
      "orcid": "0000-0002-3835-9639"
    },
    {
      "affs": [
        2
      ],
      "name": "Najaf Amin",
      "orcid": "0000-0002-8944-1771"
    },
    {
      "affs": [
        11,
        13
      ],
      "name": "Dabin Yoon"
    },
    {
      "affs": [
        5,
        18,
        6
      ],
      "name": "Itziar de Rojas",
      "orcid": "0000-0002-2148-381X"
    },
    {
      "affs": [
        1
      ],
      "name": "Pilar Álvarez Jerez",
      "orcid": "0000-0002-5812-1898"
    },
    {
      "affs": [
        19,
        20
      ],
      "name": "Victoria Álvarez",
      "orcid": "0000-0002-1916-2523"
    },
    {
      "affs": [
        21,
        22
      ],
      "name": "Beatrice Arosio",
      "orcid": "0000-0002-0615-3580"
    },
    {
      "affs": [
        3
      ],
      "name": "Céline Bellenguez",
      "orcid": "0000-0002-1240-7874"
    },
    {
      "affs": [
        23,
        24
      ],
      "name": "Sverre Bergh",
      "orcid": "0000-0001-9593-2967"
    },
    {
      "affs": [
        1
      ],
      "name": "Kimberley J. Billingsley",
      "orcid": "0000-0002-8003-4029"
    },
    {
      "affs": [
        25
      ],
      "name": "Cornelis Blauwendraat",
      "orcid": "0000-0001-9358-8111"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Merçé Boada",
      "orcid": "0000-0003-2617-3009"
    },
    {
      "affs": [
        26,
        27
      ],
      "name": "Barbara Borroni",
      "orcid": "0000-0001-9340-9814"
    },
    {
      "affs": [
        28
      ],
      "name": "Paola Bossù",
      "orcid": "0000-0002-1432-0078"
    },
    {
      "affs": [
        29,
        30,
        6
      ],
      "name": "Maria Jesus Bullido",
      "orcid": "0000-0002-6477-1117"
    },
    {
      "affs": [
        31,
        32
      ],
      "name": "Antonio Daniele"
    },
    {
      "affs": [
        33,
        34
      ],
      "name": "Ángel Carracedo",
      "orcid": "0000-0003-1085-8986"
    },
    {
      "affs": [
        35
      ],
      "name": "Alexandre de Mendonça",
      "orcid": "0000-0002-0488-1453"
    },
    {
      "affs": [
        1
      ],
      "name": "Mark Cookson",
      "orcid": "0000-0002-1058-3831"
    },
    {
      "affs": [
        36
      ],
      "name": "Jürgen Deckert",
      "orcid": "0000-0003-1008-4650"
    },
    {
      "affs": [
        37,
        38,
        39
      ],
      "name": "Martin Dichgans",
      "orcid": "0000-0002-0654-387X"
    },
    {
      "name": "Srdjan Djurovic",
      "orcid": "0000-0002-8140-8061"
    },
    {
      "affs": [
        6
      ],
      "name": "Oriol Dols‐Icardo",
      "orcid": "0000-0003-2656-8748"
    },
    {
      "name": "Carole Dufouil",
      "orcid": "0000-0003-2442-4476"
    },
    {
      "name": "Emrah Düzel",
      "orcid": "0000-0002-0139-5388"
    },
    {
      "name": "Valentina Escott‐Price",
      "orcid": "0000-0003-1784-5483"
    },
    {
      "name": "Tormod Fladby",
      "orcid": "0000-0002-9984-9797"
    },
    {
      "name": "Laura Fratiglioni",
      "orcid": "0000-0002-6374-6614"
    },
    {
      "affs": [
        14,
        15
      ],
      "name": "Amy K.Y. Fu",
      "orcid": "0000-0003-4085-6201"
    },
    {
      "name": "Daniela Galimberti",
      "orcid": "0000-0002-9284-5953"
    },
    {
      "affs": [
        6
      ],
      "name": "José María García‐Alberca",
      "orcid": "0000-0003-2951-6644"
    },
    {
      "name": "Vilmantas Giedraitis",
      "orcid": "0000-0003-3423-2021"
    },
    {
      "name": "Guillermo García‐Ribas"
    },
    {
      "name": "Caroline Graff",
      "orcid": "0000-0002-9949-2951"
    },
    {
      "name": "Timo Grimmer",
      "orcid": "0000-0002-6829-6253"
    },
    {
      "name": "Edna Grünblatt",
      "orcid": "0000-0001-8505-7265"
    },
    {
      "name": "Olivier Hanon",
      "orcid": "0000-0002-4697-122X"
    },
    {
      "name": "Lucrezia Hausner",
      "orcid": "0000-0001-9009-2356"
    },
    {
      "name": "Stefanie Heilmann‐Heimbach",
      "orcid": "0000-0003-1057-465X"
    },
    {
      "name": "Jakub Hort",
      "orcid": "0000-0002-1080-3726"
    },
    {
      "name": "Frank Jessen",
      "orcid": "0000-0003-1067-2102"
    },
    {
      "name": "Kendall Jensen"
    },
    {
      "affs": [
        1
      ],
      "name": "Caroline Jonson",
      "orcid": "0000-0001-7049-6281"
    },
    {
      "affs": [
        10,
        13
      ],
      "name": "Y T Kim",
      "orcid": "0009-0008-0913-006X"
    },
    {
      "affs": [
        1
      ],
      "name": "Nicole Kuznetsov",
      "orcid": "0009-0005-9847-0282"
    },
    {
      "name": "Ville Leinonen",
      "orcid": "0000-0002-4282-4687"
    },
    {
      "affs": [
        4
      ],
      "name": "Anssi Lipponen",
      "orcid": "0000-0002-4403-9084"
    },
    {
      "name": "Jiao Luo"
    },
    {
      "affs": [
        1
      ],
      "name": "Mary B. Makarious",
      "orcid": "0000-0002-7978-1051"
    },
    {
      "affs": [
        4
      ],
      "name": "Henna Martiskainen",
      "orcid": "0000-0003-2796-1859"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/an1cemw7jd0m5.bib",
  "cited_by": 6,
  "doi": "10.1038/s41588-026-02713-9",
  "fulltext_url": null,
  "id": "an1cemw7jd0m5",
  "issns": [
    "1061-4036",
    "1546-1718"
  ],
  "landing_url": "https://hal.science/hal-05784438v1",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "hal",
      "1.sdv.spee"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ],
    [
      "openalex",
      "2804|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7212820066",
  "pdf_url": "https://www.nature.com/articles/s41588-026-02713-9.pdf",
  "pmcid": "PMC12083631",
  "pmid": "42736378",
  "published": "2026-09-14",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/an1cemw7jd0m5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:50Z",
      "native_id": "hal-05784438",
      "source": "hal",
      "url": "https://hal.science/hal-05784438v1"
    },
    {
      "first_seen": "2026-11-06T13:20:36Z",
      "native_id": "W7212820066",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41588-026-02713-9"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "hal:0.sdv",
      "subfield": "general"
    },
    {
      "field": "medicine",
      "origin": "hal:1.sdv.spee",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "APOE-Stratified Genome-Wide Association Analyses Provide Insights into the Genetic Etiology of Alzheimers's Disease",
  "title_text": "APOE-Stratified Genome-Wide Association Analyses Provide Insights into the Genetic Etiology of Alzheimers's Disease",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:49Z",
  "url": "https://research.draconitic.com/paper/an1cemw7jd0m5",
  "venue": "Nature Genetics",
  "versions": []
}