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APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry
Open accessAbstract
Importance: Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields. Objective: To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry. Design, Setting, Participants: This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies. Main Outcomes and Measures: The main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses. Results: Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age–specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94). Conclusion and Relevance: Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.
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“Even more puzzling than these differences in APOEε4-linked AD risk are those associated with the APOEε2 allele; this study found that the protective effect of APOEε2 is attenuated in Black versus white people, whereas in Hispanic and East Asian individuals, the APOEε2 allele confers essentially no protection against AD relative to APOEε3 homozygosis, and only in the presence of APOEε4 does APOEε2”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Rather, age and sex moderate the effects of the APOE genotype on AD risk so that the risk associated with the APOEε3/ε4 genotype is highest in women of ages 60–70 years (or 70–80 years according to ref. 6) but decreases in older women and equalizes to that of non-Hispanic White, Black and Hispanic men of the same age10.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [10]
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In the citing paper
“In the analysis, APOE allele frequencies for East Asian, white, Black and Hispanic people were as follows: APOEε2 carriers 5.6%, 11.1%, 19.7% and 10.6%; APOEε3 homozygotes 72.8%, 50.6%, 43.3% and 61.3% and APOEε4 carriers 21.6%, 40.6%, 41.6% and 29.9%, respectively10.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [10]
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“Compared with E3, E4 confers up to a 13-fold increase in risk for AD in homozygous carriers1.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [1]
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“First, the degree of risk and protection afforded by E4 and E2 respectively vary according to ancestry1,59–62.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [1]
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“APOE remains the strongest common genetic determinant of late-onset Alzheimer disease (AD) 1 , but the molecular basis of its effect is still unresolved.”
From Association of Rare APOE Missense Variants R189C and W276C With Risk of Alzheimer Disease (2026) · cites this paper as [1]
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“Notably, this age × sex interaction with the APOEε3/ε4 genotype was not only seen in non-Hispanic White people but also replicated in Black and Hispanic individuals via meta-analysis of both groups, suggesting that the interaction is independent of race and ethnicity10.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [10]
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“Among the AD susceptibility genes/loci identified to date, APOE remains the most significant genetic risk factor across populations.”
From Association of rare APOE missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [10]
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Metadata
- Authors
- Belloy, M. E., Andrews, S. J., Le Guen, Y., Cuccaro, M., Farrer, L. A., Napolioni, V., & Greicius, M. D.
- Affiliations
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, California
- University of California, San Francisco (US)
- University of Miami (US)
- Boston University (US)
- Università di Camerino (IT)
- Stanford University (US)
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2023-12-01
- Volume
- 80
- Issue
- 12
- Pages
- 1284
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC10628838
- OpenAlex
- W4388410342
- Cited by
- 320
- References
- 38
- Citations by year
- 2026: 120 · 2025: 149 · 2024: 47 · 2023: 4
- FWCI
- 56.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Neurology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Unicam Scientific Publications (University of Camerino) (submittedVersion, cc-by)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- Funders
- Alzheimer's Association (AARF-20-683984)
- European Commission (890650)
- National Institute on Aging (R01AG060747, P50AG047366, K99AG075238, U24AG021886, R00AG075238)
- H2020 Marie Skłodowska-Curie Actions
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- apolipoprotein E, APOE ε4, late-onset Alzheimer's disease, Alzheimer's disease risk, sex differences, age effects, population ancestry, racial and ethnic disparities, East Asian populations, Hispanic population, non-Hispanic Black population, non-Hispanic whites, genetic risk stratification, clinical trial design
- MeSH terms
- Aged, Alzheimer Disease, Antibodies, Monoclonal, Apolipoproteins E, Female, Genotype, Humans, Male, Middle Aged, Amyloid beta-Peptides, White People, Apolipoprotein E4
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