Impact of Depression on Alzheimer's disease: Prenatal Immune Origins and Shared Impact of Sex

抑郁症对阿尔茨海默病的影响：产前免疫起源和性别的共同影响 项目摘要 随着人口老龄化的大幅增加，早期预防阿尔茨海默病（AD）是 我们这个时代最重要的公共卫生和经济挑战。AD与重度抑郁症相关 两种疾病（MDD）的发病率女性都是男性的两倍。然而，共同的病理生理学 这是MDD和AD的基础，并不为人所知。我们将检验这一共同风险起源于胎儿的假设 这涉及免疫应激和血管通路的异常，其后果取决于性别。我们 独特地准备在人类中首次使用我们的60年前瞻性产前队列研究， 成年人，从妊娠中期/妊娠晚期开始随访，最近在MH 090291中对44-57岁的成年人进行了检测。在这 研究中，我们调查了胎儿编程的性别差异在记忆电路老化，以下212 不一致的兄弟姐妹（一个暴露于先兆子痫（PE）或胎儿生长受限（FGR），另一个未暴露） 其中，我们发现PE/FGR与母体产前TNF-α、IL-10、TNF-α和IL-12的免疫激活异常有关。 10和IL-6。我们建议进一步跟踪这些兄弟姐妹，以研究中年记忆力下降超过8 年，神经血管功能障碍和临床前AD病理学评估为淀粉样蛋白沉积。我们将使用 与MH 090291中相同的多模态成像（结构、功能和弥散脑成像-- sMRI/fMRI/dMRI）和相同的言语学习/记忆测量，加上新的 基于视网膜成像的神经血管功能，成年后代的新转录组学分析 外周血单核细胞测量先天免疫基因表达和淀粉样蛋白沉积 PiB PET成像。我们假设，产前母体生物标志物，表明在子宫内免疫破坏， 妊娠中期，再加上先天免疫基因的表达，将与性别依赖的成人结局有关 在中年后期。此外，我们将测试产前炎症生物标志物与性别之间的关系- 依赖性AD风险和神经血管失调由MDD的性别依赖性风险介导。我们的寿命 观点是一种创新的方法，将确定潜在的治疗目标，为AD相关的 MDD和血管功能具有性别依赖性，可应用于早期干预， 发病

“Impact of Depression on Alzheimer's disease: Prenatal Immune Origins and Shared Impact of Sex” Project Summary With the substantial increase in aging of the population, early prevention of Alzheimer’s disease (AD) is one of the most important public health and economic challenges of our time. AD is associated with major depressive disorder (MDD), and both have twice the frequency in women than men. However, the shared pathophysiology that underlies MDD and AD is not well known. We will test the hypothesis that this shared risk has fetal origins that involve abnormalities in immune-stress and vascular pathways with sex-dependent consequences. We are uniquely poised to examine this for the first time in humans using our 60-year prospective prenatal cohort of adults, followed since 2nd/3rd trimesters of gestation and tested recently at ages 44-57 in MH090291. In that study, we investigated the fetal programming of sex differences in memory circuitry aging, following 212 discordant siblings (one exposed to preeclampsia (PE) or fetal growth restriction (FGR) and one unexposed) wherein we showed PE/FGR associated with maternal prenatal immune activation abnormalities in TNF-, IL- 10, and IL-6. We propose to follow these siblings further to investigate later midlife memory decline over 8 years, neurovascular dysfunction, and preclinical AD pathology assessed as amyloid deposition. We will use the same multimodal imaging as in MH090291 (structural, functional, and diffusion brain imaging-- sMRI/fMRI/dMRI) and same measures of verbal learning/memory, coupled with new measures of neurovascular function based on retinal imaging, novel transcriptomic analyses in the adult offspring’s peripheral blood mononuclear cells measuring innate immune gene expression, and amyloid deposition based on PiB PET imaging. We postulate that prenatal maternal biomarkers, indicating in utero immune disruptions at mid-gestation, coupled with innate immune gene expression, will be related to sex-dependent adult outcomes in later midlife. Further, we will test whether associations between prenatal inflammatory biomarkers and sex- dependent AD risk and neurovascular dysregulation are mediated by sex-dependent risk for MDD. Our lifespan perspective is an innovative approach that will identify potential therapeutic targets for AD associated with MDD and vascular function that are sex-dependent and can be applied to early periods for intervention prior to disease onset.