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APOE4 homozygosity represents a distinct genetic form of Alzheimer’s disease
Open accessAbstract
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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“APOE is a lipoprotein involved in the transport of cholesterol and phospholipids between cells, and allelic variation in the APOE gene is a strong genetic risk factor for AD [16, 44].”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [16]
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“The isoform variation of the protein is associated with an increased risk of developing AD in the general population [11, 16, 44].”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [16]
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“APOE4 is the strongest genetic risk factor for AD not only increasing the odds ratio of developing the disease but also lowering the age of onset in a dose-dependent fashion.17, 18”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [18]
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“APOE4 is the strongest genetic risk factor for AD not only increasing the odds ratio of developing the disease but also lowering the age of onset in a dose-dependent fashion.17, 18”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [18]
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In the citing paper
“APOE4 is the strongest genetic risk factor for AD not only increasing the odds ratio of developing the disease but also lowering the age of onset in a dose-dependent fashion.17, 18”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [18]
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“Although APOEε4 homozygosity may approach 100% penetrance for Aβ deposition in the brain16, even for white or East Asian people, being homozygous for APOEε4 is not synonymous with developing AD dementia”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [16]
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“APOE is a lipoprotein involved in the transport of cholesterol and phospholipids between cells, and allelic variation in the APOE gene is a strong genetic risk factor for AD [16, 44].”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [16]
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Metadata
- Authors
- Fortea, J., Pegueroles, J., Alcolea, D., Belbin, O., Dols-Icardo, O., Vaqué-Alcázar, L., Videla, L., Gispert, J. D., Suárez-Calvet, M., Johnson, S. C., Sperling, R., Bejanin, A., Lleó, A., & Montal, V.
- Affiliations
- Hospital de Sant Pau (ES)
- Universitat Pompeu Fabra (ES)
- University of Wisconsin–Madison (US)
- Brigham and Women's Hospital (US)
- Barcelona Supercomputing Center (ES)
- Corresponding author
- Fortea, Juan
- Montal, Víctor
- ORCID
- Venue
- Nature Medicine
- Published
- 2024-05
- Volume
- 30
- Issue
- 5
- Pages
- 1284-1291
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC13310155
- OpenAlex
- W4396673676
- Cited by
- 369
- References
- 32
- Citations by year
- 2026: 110 · 2025: 191 · 2024: 67
- FWCI
- 104.73
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-06-17)
- Open access
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- U.S. Department of Health and Human Services (U54HD090256, P01AG036694 and P50AG005134, R21 AG056974, R01 AG027161, S10 OD025245, UF1AG051216, P50 AG033514, and P30 AG062715, UL1 TR002373, P30 AG062715, R01 AG061566, R01 AG054059, R01 AG037639)
- Alzheimer's Association (AARG-22-923680)
- European Commission (948677 and 847648, H2020-SC1-BHC-2018-2020, Grant 2021)
- Generalitat de Catalunya (SLT006/17/00119, SLT002/16/00408)
- Ministerio de Economía y Competitividad (PI22/00307, PI20/01330, PI20/01473, PI18/00435, PI22/00456)
- Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona (LCF/PR/GN17/50300004)
- National Institutes of Health (5u01ag024904-10, 1s10od025245-01, UL1TR002373)
- National Institute on Aging (U01-AG-024904, R01AG081394, UF1AG051216, RF1AG056850, R61AG066543, R01AG037639, R01AG063689, P50AG033514, RF1AG061566, P50AG005134, R21AG056974, R01AG021155, R01AG027161, U24AG057437, P01AG036694, R01AG054059, P30AG062715, U24AG072122)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090256)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Alzheimer's disease, APOE3, amyloid PET, cerebrospinal fluid amyloid, tau PET, symptom onset age, disease progression, autosomal dominant Alzheimer's disease, Down syndrome, penetrance, dementia stages
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Apolipoproteins E, Female, Homozygote, Humans, Male, Middle Aged, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Age of Onset, Positron-Emission Tomography, Apolipoprotein E3, Apolipoprotein E4
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