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


This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer’s disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer’s Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.

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Fig. 1: Penetrance and predictive value of APOE4 homozygosity in AD.
Fig. 2: Comparative survival analysis of clinical symptom onset and mortality by age, across different APOE haplotypes.
Fig. 3: Changes in AD biomarkers in APOE3 and APOE4 homozygotes with age.
Fig. 4: Integrated model of the natural history of AD biomarker changes in APOE4 homozygotes.
Fig. 5: Biomarker changes in patients with AD dementia.

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Data availability

Access to tabular data from ADNI (, OASIS (, A4 ( and NACC ( can be requested online, as publicly available databases. All requests will be reviewed by each studyʼs scientific board. Concrete inquiries to access the WRAP ( and ALFA + ( 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 (ref. 32). For neuroimaging analyses, we used Free Surfer (v.6.0) and ANTs (v.2.4.0).


  1. Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 54, 412–436 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Frisoni, G. B. et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat. Rev. Neurosci. 23, 53–66 (2022).

    Article  CAS  PubMed  Google Scholar 

  3. Bateman R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012).

  4. Genin, E. et al. APOE and Alzheimer disease: a major gene with semidominant inheritance. Mol. Psychiatry 16, 903–907 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fortea, J. et al. Alzheimer’s disease associated with Down syndrome: a genetic form of dementia. Lancet Neurol. 20, 930–942 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fortea, J. et al. Clinical and biomarker changes of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study. Lancet 395, 1988–1997 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313, 1924–1938 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Saddiki H. et al. Age and the association between apolipoprotein E genotype and Alzheimer disease: a cerebrospinal fluid biomarker-based case-control study. PLoS Med. (2020).

  9. Jack, C. R. et al. NIA‐AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement. 14, 535–562 (2018).

    Article  Google Scholar 

  10. Beekly, D. L. et al. The National Alzheimer’s Coordinating Center (NACC) Database: an Alzheimer disease database. Alzheimer Dis. Assoc. Disord. 18, 270–277 (2004).

    PubMed  Google Scholar 

  11. Montine, T. J. et al. National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol. 123, 1–11 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Reiman, E. M. et al. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat. Commun. 11, 1–11 (2020).

    Article  Google Scholar 

  13. Iulita M. F. et al. Association of Alzheimer disease with life expectancy in people with Down syndrome. JAMA Netw. Open (2022).

  14. Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Fortea, J., Quiroz, Y. T. & Ryan, N. S. Lessons from Down syndrome and autosomal dominant Alzheimer’s disease. Lancet Neurol. 22, 5–6 (2023).

    Article  CAS  PubMed  Google Scholar 

  16. Therriault, J. et al. Frequency of biologically defined Alzheimer’s disease in relation to age, sex, APOE ε4, and cognitive impairment. Neurology 96, e975–e985 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Betthauser, T. J. et al. Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts. Brain 145, 4065–4079 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Snellman, A. et al. APOE ε4 gene dose effect on imaging and blood biomarkers of neuroinflammation and beta-amyloid in cognitively unimpaired elderly. Alzheimers Res. Ther. 15, 71 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ghisays, V. et al. Brain imaging measurements of fibrillar amyloid-β burden, paired helical filament tau burden, and atrophy in cognitively unimpaired persons with two, one, and no copies of the APOE ε4 allele. Alzheimers Dement. 16, 598–609 (2020).

  20. Mehta, R. I. & Schneider, J. A. What is ‘Alzheimer’s disease’? The neuropathological heterogeneity of clinically defined Alzheimer’s dementia. Curr. Opin. Neurol. 34, 237–245 (2021).

    Article  CAS  PubMed  Google Scholar 

  21. van der Lee, S. J. et al. The effect of APOE and other common genetic variants on the onset of Alzheimer’s disease and dementia: a community-based cohort study. Lancet Neurol. 17, 434–444 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Belloy, M. E., Napolioni, V. & Greicius, M. D. A quarter century of APOE and Alzheimera’s disease: progress to date and the path forward. Neuron 101, 820–838 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Belloy, M. E. et al. APOE genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurol. 80, 1284–1294 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jack, C. R. et al. Long-term associations between amyloid positron emission tomography, sex, apolipoprotein E and incident dementia and mortality among individuals without dementia: hazard ratios and absolute risk. Brain Commun. 4, fcac017 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Morris, J. C. The Clinical Dementia Rating (CDR): current version and scoring rules.Neurology 43, 2412–2414 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Weiner, M. W. et al. The Alzheimer’s Disease Neuroimaging Initiative 3: continued innovation for clinical trial improvement. Alzheimer’s Dement. 13, 561–571 (2017).

    Article  Google Scholar 

  27. Sperling R. A. et al. The A4 Study: stopping AD before symptoms begin? Sci. Transl. Med. (2014).

  28. Molinuevo, J. L. et al. The ALFA project: a research platform to identify early pathophysiological features of Alzheimer’s disease. Alzheimer’s Dement.: Transl. Res. Clin. Interventions 2, 82–92 (2016).

    Article  Google Scholar 

  29. Johnson, S. C. et al. The Wisconsin Registry for Alzheimer’s Prevention: a review of findings and current directions. Alzheimer’s Dement.: Diagnosis, Assess. Dis. Monit. 10, 130–142 (2018).

    Google Scholar 

  30. LaMontagne P. J. et al. OASIS-3: longitudinal neuroimaging, clinical and cognitive dataset for normal aging and Alzheimer disease. Preprint at MedRxiv (2019).

  31. La Joie, R. et al. Multisite study of the relationships between antemortem [11C]PIB-PET Centiloid values and postmortem measures of Alzheimer’s disease neuropathology. Alzheimers Dement. 15, 205–216 (2019).

  32. Montal, V. APOE4-ASDAD. GitLab (2024).

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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

Authors and Affiliations



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.

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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 30, 1284–1291 (2024).

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