The Association Between APOE Genotype, Race, and Dementia: An Analysis of 7 Population-Based Cohort Studies.

Authors

Natalia Lakomski, Katherine Giorgio, John Stephen, Maxwell Mansolf, Aïcha Soumaré, Alden L Gross, Allison E Aiello, Archana Singh-Manoux, M Arfan Ikram, Catherine Helmer, Claudia L Satizabal, Deborah A Levine, Donald M Lloyd-Jones, Emily M Briceño, Farzaneh A Sorond, Frank J Wolters, Jayandra J Himali, Lenore J Launer, Djass Mbangdadji, David Li, Lihui Zhao, Oscar L Lopez, Stéphanie Debette, Sudha Seshadri, Suzanne E Judd, Timothy M Hughes, Vilmundur Guðnason, Michael Griswold, Paul S de Vries, Alison Fohner, Pamela L Lutsey, Rachel Zmora, Elizabeth A Peterson, Denise Scholtens, Norrina B Allen, Sanaz Sedaghat

Published in

Neurology. Genetics. Volume 12. Issue 4. Pages e200417. Epub Jul 16, 2026.

Abstract

The apolipoprotein E (APOE) haplotypes are known to be associated with dementia, with the ε4 haplotype associated with higher risk. It has been suggested that the APOE ε2 allele serves as a protective factor for dementia. However, data on the effects of the homozygous APOE ε2/ε2 genotype are limited, likely due to the rarity of the APOE ε2/ε2 genotype. Furthermore, the association between APOE genotypes and dementia may differ across self-reported race. We aim to investigate the association between APOE genotypes and dementia overall and across self-reported race, with a focus on the potential protective effects of the ε2 haplotype and differences across race.
Data from 7 large, community-based, prospective cohort studies from the Dementia Risk Prediction Pooling Project: Age, Gene/Environment Susceptibility-Reykjavik Study, Whitehall II study, Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Honolulu-Asia Aging Study, Multi-Ethnic Study of Atherosclerosis, and Framingham Heart Study and its associated cohorts were used. Cox proportional hazard models were used to estimate the cause-specific hazard ratios of dementia by APOE genotypes overall and by self-reported race.
The study consisted of 45,022 participants (10% Asian, 15% Black, 75% White, 52% male) with a mean age of 56 years (SD: 14.5) at baseline. Compared with participants with an APOE ε3/ε3 genotype, those with an ε2/ε3 genotype had a lower risk of dementia (HR: 0.87, 95% CI 0.80-0.96). There was an indication of protective effects of the ε2/ε2 genotype compared with the ε3/ε3 genotype (HR: 0.98, 95% CI 0.71-1.37). These associations were similar among Black and White participants. The detrimental effect of an ε4/ε4 genotype compared with an ε3/ε3 genotype was also seen overall and among Black and White participants. Those with an APOE ε4/ε4 genotype experienced dementia onset approximately 8 years earlier than those with an APOE ε3/ε3 genotype.
In this large, pooled cohort, the presence of at least one APOE ε2 allele was associated with lower risk of dementia overall and by self-reported race, suggesting a protective effect. APOE ε4/ε4 was associated with an earlier age of dementia onset with differences across race.

PMID:
42519715
Bibliographic data and abstract were imported from PubMed on 29 Jul 2026.

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