Variation in APOE ε4 Prevalence and Brain Health Associations by European Descent in White All of Us Participants.

IMPORTANCE

The ε4 allele is among the best-established genetic risk factor for Alzheimer's disease. Different ethnic and racial groups have varying ε4 prevalences. The prevalence of ε4 also varies among European regions, yet White Americans are treated as a monolith, potentially impacting recruitment decisions and risk profile estimations.

OBJECTIVE

To test whether White Americans of Southern European descent have a lower prevalence of ε4 than their Northern European descent peers, and secondarily, if ε4-brain health outcomes vary by European descent.

DESIGN SETTING AND PARTICIPANTS

Cross-sectional analyses of the nationwide All of Us cohort study in the United States. Overall inclusion criteria were reporting only White race, and countries of descent from Northern, Central or Southern Europe without overlap. Enrollment opened in May 2018. Analyses were conducted April-June 2025.

EXPOSURES

Regions of European descent (Northern, Central and Southern) from the Basics Survey.

MAIN OUTCOMES AND MEASURES

APOE ε4 using variants rs429358 and rs7412, coded as zero, one or two copies.

RESULTS

Among those aged ≥18 (n=77,676), the percentage of European descent was 7.7% Southern and 64.7% Northern. Age and female sex at birth were 55.5 years and 55.8% among Americans of Southern and 56.3 years and 57.4% among those of Northern European descent. APOE ε4 allele frequency was 17.4% for one and 0.1% for two copies among Americans of Southern, and 24.9% and 2.0% for Northern European descent. Logistic regression models confirmed these differences: compared to Americans of Southern European descent, those of Northern European descent had an Odds Ratio of having one APOE ε4 allele of 1.60 (1.49-1.71), and 2.21 (1.71-2.88) of having two APOE ε4 alleles. European descent moderated associations between APOE ε4 allele frequency and two brain health outcomes (interaction p≤0.10).

CONCLUSIONS AND RELEVANCE

The frequency of ε4 among Americans of Southern European descent was lower than that of Northern European descent and associations with some brain health outcomes varied. Future studies need to use probabilistic samples to confirm these findings. The concept of White race might be too broad when making racial comparisons of ε4 frequency and its effects.