Choi Eun Young, Cho Gawon, Chang Virginia W
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA.
Yale School of Medicine, Yale University, New Haven, Connecticut, USA.
J Am Geriatr Soc. 2025 Sep 14. doi: 10.1111/jgs.70086.
Early life is a critical period for brain development, laying the foundation for cognitive reserve. However, it remains unclear how various aspects of early life independently contribute to dementia risk, and whether these associations are modified by APOE ε4 genotype.
We used data from the U.S. Health and Retirement Study (HRS), a nationally representative cohort of older adults, followed from 2006 to 2020. Our sample included 8678 community-dwelling, dementia-free participants aged ≥ 60 and < 90 at baseline with data on APOE genotype and retrospective early life conditions.
Dementia incidence was classified using the validated Langa-Weir algorithm. Early life risk domains included financial capital, social capital, human capital, adversity, and health conditions. Cause-specific Cox proportional hazards models assessed the associations between these domains and incident dementia, adjusting for demographics and adulthood risk factors. To examine effect modification by genetic risk, we created 4-category group variables combining APOE ε4 status and early life risk.
Deficits in financial, social, and human capital, as well as poor childhood health, were each associated with a 12%-46% increased dementia risk, independently of APOE ε4 status. After further adjusting for adulthood risk factors, low social and human capital remained significant predictors (16% and 21% increased risk, respectively). APOE ε4 was associated with an 83%-86% increased risk across all models. In effect modification analyses, early life disadvantage was associated with dementia only among non-carriers of APOE ε4, whereas ε4 carriers had elevated dementia risk regardless of early life conditions.
Inadequate childhood resources may have enduring impacts on dementia risk among individuals without the APOE ε4 allele. Genetic predisposition via APOE ε4 overwhelms the influence of early life disadvantage. These findings underscore the need for dementia prevention strategies that jointly consider genetic vulnerability and early life conditions.
早年是大脑发育的关键时期，为认知储备奠定基础。然而，目前尚不清楚早年生活的各个方面如何独立影响痴呆风险，以及这些关联是否会因APOE ε4基因型而改变。
我们使用了美国健康与退休研究（HRS）的数据，该研究是一个具有全国代表性的老年人队列，随访时间为2006年至2020年。我们的样本包括8678名居住在社区、基线时年龄≥60岁且<90岁、无痴呆症的参与者，他们有APOE基因型数据和回顾性早年生活状况数据。
使用经过验证的Langa-Weir算法对痴呆发病率进行分类。早年生活风险领域包括金融资本、社会资本、人力资本、逆境和健康状况。特定病因的Cox比例风险模型评估这些领域与痴呆症发病之间的关联，并对人口统计学和成年期风险因素进行调整。为了检验基因风险的效应修正作用，我们创建了结合APOE ε4状态和早年生活风险的4类分组变量。
金融、社会和人力资本的不足，以及童年健康状况不佳，均与痴呆风险增加12%-46%相关，且独立于APOE ε4状态。在进一步调整成年期风险因素后，低社会资本和低人力资本仍然是显著的预测因素（风险分别增加16%和21%）。在所有模型中，APOE ε4与风险增加83%-86%相关。在效应修正分析中，早年生活劣势仅在APOE ε4非携带者中与痴呆症相关，而ε4携带者无论早年生活状况如何，痴呆风险均升高。
童年资源不足可能对没有APOE ε4等位基因的个体的痴呆风险产生持久影响。通过APOE ε4的遗传易感性掩盖了早年生活劣势的影响。这些发现强调了需要联合考虑遗传易感性和早年生活状况的痴呆预防策略。
