Perales-Puchalt Jaime, Mansel Clayton O, Veatch Olivia J
University of Kansas Alzheimer's Disease Research Center; University of Kansas Medical Center; Kansas, USA.
Department of Cell Biology and Physiology, University of Kansas Medical Center; Kansas, USA.
medRxiv. 2025 Jul 17:2025.07.16.25331679. doi: 10.1101/2025.07.16.25331679.
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.
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.
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.
Regions of European descent (Northern, Central and Southern) from the Basics Survey.
APOE ε4 using variants rs429358 and rs7412, coded as zero, one or two copies.
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).
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.
ε4等位基因是阿尔茨海默病已明确的最佳遗传风险因素之一。不同种族和民族群体的ε4流行率各不相同。ε4在欧洲不同地区的流行率也有所差异，但美国白人被视为一个整体，这可能会影响招募决策和风险特征评估。
检验南欧裔美国白人的ε4流行率是否低于北欧裔同龄人，其次，ε4与大脑健康结果之间的关系是否因欧洲血统而异。
设计、设置和参与者：对美国全国性的“我们所有人”队列研究进行横断面分析。总体纳入标准是仅报告白人种族，且来自北欧、中欧或南欧的祖籍国无重叠。2018年5月开始招募。2025年4月至6月进行分析。
基础调查中的欧洲祖籍地区（北欧、中欧和南欧）。
使用rs429358和rs7412变体检测APOE ε4，编码为零、一或两个拷贝。
在年龄≥18岁的人群中（n = 77,676），南欧裔占7.7%，北欧裔占64.7%。南欧裔美国人的年龄和出生时的女性比例分别为55.5岁和55.8%，北欧裔分别为56.3岁和57.4%。南欧裔美国人中APOE ε4等位基因频率为一个拷贝时为17.4%，两个拷贝时为0.1%；北欧裔分别为24.9%和2.0%。逻辑回归模型证实了这些差异：与南欧裔美国人相比，北欧裔美国人携带一个APOE ε4等位基因的优势比为1.60（1.49 - 1.71），携带两个APOE ε4等位基因的优势比为2.21（1.71 - 2.88）。欧洲血统调节了APOE ε4等位基因频率与两种大脑健康结果之间的关联（交互作用p≤0.10）。
南欧裔美国白人中ε4的频率低于北欧裔，且与某些大脑健康结果的关联存在差异。未来研究需要使用概率样本以证实这些发现。在对ε4频率及其影响进行种族比较时，白人种族的概念可能过于宽泛。
