With an increasing aging population and Alzheimer’s disease tsunami, it is critical to identify early antecedents of brain aging to target for intervention and prevention. Women and men develop and age differently, thus using a sex differences lens can contribute to identification of early risk biomarkers and resilience. There is growing evidence for fetal antecedents to adult memory impairments, potentially through disruption of maternal prenatal immune pathways. Here, we hypothesized that in utero exposure to maternal pro-inflammatory cytokines will have sex-dependent effects on specific brain circuitry regulating offspring’s memory and immune function that will be retained across the lifespan. Using a unique prenatal cohort, we tested this in 204 adult offspring, equally divided by sex, who were exposed/unexposed to an adverse in utero maternal immune environment and followed into early midlife (~age 50). Functional magnetic resonance imaging results showed exposure to pro-inflammatory cytokines in utero (i.e., higher maternal IL-6 and TNF-α levels) was significantly associated with sex differences in brain activity and connectivity underlying memory circuitry and performance and with a hyperimmune state, 50 years later. In contrast, the anti-inflammatory cytokine, IL-10 alone, was not significantly associated with memory circuitry in midlife. Predictive validity of prenatal exposure was underscored by significant associations with age 7 academic achievement, also associated with age 50 memory performance. Results uniquely demonstrated that adverse levels of maternal in utero pro-inflammatory cytokines during a critical period of the sexual differentiation of the brain produced long-lasting effects on immune function and memory circuitry/function from childhood to midlife that were sex-dependent, brain region-specific, and, within women, reproductive stage-dependent.

随着人口老龄化和阿尔茨海默病海啸的加剧，确定大脑衰老的早期前因以作为干预和预防的目标至关重要。女性和男性的发育和衰老不同，因此使用性别差异镜片有助于识别早期风险生物标志物和恢复力。越来越多的证据表明，胎儿先因成人记忆障碍，可能是通过破坏母体产前免疫途径。在这里，我们假设在子宫内暴露于母体促炎细胞因子会对调节后代记忆和免疫功能的特定大脑回路产生性别依赖性影响，这些影响将在整个生命周期中保留。使用一个独特的产前队列，我们在 204 名成年后代中对此进行了测试，这些后代按性别平均分配，他们暴露于/未暴露于不利的子宫内母体免疫环境，并随访到中年早期 （~50 岁）。功能性磁共振成像结果显示，在子宫内暴露于促炎细胞因子（即较高的母体 IL-6 和 TNF-α 水平）与大脑活动和连接性（基础记忆回路和性能）的性别差异显著相关，并与 50 年后的超免疫状态相关。相比之下，单独的抗炎细胞因子 IL-10 与中年人的记忆回路没有显着关联。与 7 岁学业成绩的显着关联强调了产前暴露的预测有效性，也与 50 岁的记忆表现相关。 结果独特地表明，在大脑性分化的关键时期，母体子宫内促炎细胞因子的不良水平对免疫功能和记忆回路/功能产生了长期影响，这些影响是性别依赖性的，大脑区域特异性的，并且在女性中，生殖阶段依赖性。