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

Language

English

Publication Date

8-1-2026

Journal

Neurology Genetics

DOI

10.1212/NXG.0000000000200417

PMID

42519715

PMCID

PMC13382979

PubMedCentral® Posted Date

7-16-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Background and objectives: 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.

Methods: 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.

Results: 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.

Discussion: 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.

Published Open-Access

yes

Recommended Citation

Lakomski, Natalia; Giorgio, Katherine; Stephen, John; et al., "The Association Between APOE Genotype, Race, and Dementia: An Analysis of 7 Population-Based Cohort Studies" (2026). Faculty, Staff and Student Publications. 828.
https://digitalcommons.library.tmc.edu/uthsph_docs/828