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APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease

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Data availability

Access to tabular data from ADNI (https://adni.loni.usc.edu/), OASIS (https://oasis-brains.org/), A4 (https://ida.loni.usc.edu/collaboration/access/appLicense.jsp) and NACC (https://naccdata.org/) can be requested online, as publicly available databases. All requests will be reviewed by each studyʼs scientific board. Concrete inquiries to access the WRAP (https://wrap.wisc.edu/data-requests-2/) and ALFA + (https://www.barcelonabeta.org/en/alfa-study/about-the-alfa-study) cohort data can be directed to each study team for concept approval and feasibility consultation. Requests will be reviewed to verify whether the request is subject to any intellectual property.

Code availability

All statistical analyses and raw figures were generated using R (v.4.2.2). We used the open-sourced R packages of ggplot2 (v.3.4.3), dplyr (v.1.1.3), ggstream (v.0.1.0), ggpubr (v.0.6), ggstatsplot (v.0.12), Rmisc (v.1.5.1), survival (v.3.5), survminer (v.0.4.9), gtsummary (v.1.7), epitools (v.0.5) and statsExpression (v.1.5.1). Rscripts to replicate our findings can be found at https://gitlab.com/vmontalb/apoe4-asdad (ref. 32). For neuroimaging analyses, we used Free Surfer (v.6.0) and ANTs (v.2.4.0).

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Acknowledgements

We acknowledge the contributions of several consortia that provided data for this study. We extend our appreciation to the NACC, the Alzheimer's Disease Neuroimaging Initiative, The A4 Study, the ALFA Study, the Wisconsin Register for Alzheimer's Prevention and the OASIS3 Project. Without their dedication to advancing Alzheimer's disease research and their commitment to data sharing, this study would not have been possible. We also thank all the participants and investigators involved in these consortia for their tireless efforts and invaluable contributions to the field. We also thank the institutions that funded this study, the Fondo de Investigaciones Sanitario, Carlos III Health Institute, the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas and the Generalitat de Catalunya and La Caixa Foundation, as well as the NIH, Horizon 2020 and the Alzheimer's Association, which was crucial for this research. Funding: National Institute on Aging. This study was supported by the Fondo de Investigaciones Sanitario, Carlos III Health Institute (INT21/00073, PI20/01473 and PI23/01786 to J.F., CP20/00038, PI22/00307 to A.B., PI22/00456 to M.S.-C., PI18/00435 to D.A., PI20/01330 to A.L.) and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Program 1, partly jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una Manera de Hacer Europa. This work was also supported by the National Institutes of Health grants (R01 AG056850; R21 AG056974, R01 AG061566, R01 AG081394 and R61AG066543 to J.F., S10 OD025245, P30 AG062715, U54 HD090256, UL1 TR002373, P01 AG036694 and P50 AG005134 to R.S.; R01 AG027161, R01 AG021155, R01 AG037639, R01 AG054059; P50 AG033514 and P30 AG062715 to S.J.) and ADNI (U01 AG024904), the Department de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca I Innovació en Salut (SLT006/17/00119 to J.F.; SLT002/16/00408 to A.L.) and the A4 Study (R01 AG063689, U24 AG057437 to R.A.S). It was also supported by Fundación Tatiana Pérez de Guzmán el Bueno (IIBSP-DOW-2020-151 o J.F.) and Horizon 2020-Research and Innovation Framework Programme from the European Union (H2020-SC1-BHC-2018-2020 to J.F.; 948677 and 847648 to M.S.-C.). La Caixa Foundation (LCF/PR/GN17/50300004 to M.S.-C.) and EIT Digital (Grant 2021 to J.D.G.) also supported this work. The Alzheimer Association also participated in the funding of this work (AARG-22-923680 to A.B.) and A4/LEARN Study AA15-338729 to R.A.S.). O.D.-I. receives funding from the Alzheimer's Association (AARF-22-924456) and the Jerome Lejeune Foundation postdoctoral fellowship.

Author information

Author notes

  1. These authors contributed equally: Juan Fortea, Víctor Montal.

Authors and Affiliations

  1. Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau, Barcelona, Spain

    Juan Fortea, Jordi Pegueroles, Daniel Alcolea, Olivia Belbin, Oriol Dols-Icardo, Lídia Vaqué-Alcázar, Laura Videla, Alexandre Bejanin, Alberto Lleó & Víctor Montal

  2. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas. CIBERNED, Barcelona, Spain

    Juan Fortea, Jordi Pegueroles, Daniel Alcolea, Olivia Belbin, Oriol Dols-Icardo, Laura Videla, Alexandre Bejanin, Alberto Lleó & Víctor Montal

  3. Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain

    Juan Fortea & Laura Videla

  4. Department of Medicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain

    Lídia Vaqué-Alcázar

  5. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain

    Juan Domingo Gispert & Marc Suárez-Calvet

  6. Neurosciences Programme, IMIM - Hospital del Mar Medical Research Institute, Barcelona, Spain

    Juan Domingo Gispert & Marc Suárez-Calvet

  7. Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain

    Juan Domingo Gispert & Marc Suárez-Calvet

  8. Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina. Instituto de Salud carlos III, Madrid, Spain

    Juan Domingo Gispert & Marc Suárez-Calvet

  9. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    Juan Domingo Gispert & Marc Suárez-Calvet

  10. Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA

    Sterling C. Johnson

  11. Brigham and Women's Hospital Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Reisa Sperling

  12. Barcelona Supercomputing Center, Barcelona, Spain

    Víctor Montal

Contributions

J.F. and V.M. conceptualized the research project and drafted the initial manuscript. V.M., J.P. and J.F. conducted data analysis, interpreted statistical findings and created visual representations of the data. O.B. and O.D.-I. provided valuable insights into the genetics of APOE. L.V., A.B. and L.V.-A. meticulously reviewed and edited the manuscript for clarity, accuracy and coherence. J.D.G., M.S.-C., S.J. and R.S. played pivotal roles in data acquisition and securing funding. A.L. and D.A. contributed to the study design, offering guidance and feedback on statistical analyses, and provided critical review of the paper. All authors carefully reviewed the manuscript, offering pertinent feedback that enhanced the study's quality, and ultimately approved the final version.

Corresponding authors

Correspondence to Juan Fortea or Víctor Montal.

Ethics declarations

Competing interests

S.C.J. has served at scientific advisory boards for ALZPath, Enigma and Roche Diagnostics. M.S.-C. has given lectures in symposia sponsored by Almirall, Eli Lilly, Novo Nordisk, Roche Diagnostics and Roche Farma, received consultancy fees (paid to the institution) from Roche Diagnostics and served on advisory boards of Roche Diagnostics and Grifols. He was granted a project and is a site investigator of a clinical trial (funded to the institution) by Roche Diagnostics. In-kind support for research (to the institution) was received from ADx Neurosciences, Alamar Biosciences, Avid Radiopharmaceuticals, Eli Lilly, Fujirebio, Janssen Research & Development and Roche Diagnostics. J.D.G. has served as consultant for Roche Diagnostics, receives research funding from Hoffmann-La Roche, Roche Diagnostics and GE Healthcare, has given lectures in symposia sponsored by Biogen, Philips Nederlands, Esteve and Life Molecular Imaging and serves on an advisory board for Prothena Biosciences. R.S. has received personal consulting fees from Abbvie, AC Immune, Acumen, Alector, Bristol Myers Squibb, Janssen, Genentech, Ionis and Vaxxinity outside the submitted work. O.B. reported receiving personal fees from Adx NeuroSciences outside the submitted work. D.A. reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica and Esteve, outside the submitted work. A.L. has served as a consultant or on advisory boards for Almirall, Fujirebio-Europe, Grifols, Eisai, Lilly, Novartis, Roche, Biogen and Nutricia, outside the submitted work. J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche and outside the submitted work. O.B., D.A., A.L. and J.F. report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). The remaining authors declare no competing interests.

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Nature Medicine thanks Naoyuki Sato, Yadong Huang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jerome Staal, in collaboration with the Nature Medicine team.

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Fortea, J., Pegueroles, J., Alcolea, D. et al. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Nat Med (2024). https://doi.org/10.1038/s41591-024-02931-w

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