Impact of sex differences in immune function on shared risk for cardiometabolic disorder & Alzheimer's disease

摘要 到2050年，预计美国约有1380万人患有阿尔茨海默病(AD)，其中两人- 其中三分之一将是女性。继发于遗传学的心脏代谢性疾病(CMD)，如高血压 和糖尿病，是AD的主要独立危险因素。在病理上有显著的性别差异， 这些疾病在中年早期出现的时间和临床表现。尽管如此，共同的病理生理学 潜在的CMD和AD，以及其中的性别差异，在很大程度上是未被探索的。在这里，我们将测试 假设免疫病理生理学中的性别差异在一定程度上是性别依赖的基础 心脏代谢功能障碍对中年AD风险的影响。我们计划招聘240人，年龄50岁- 75人，按性别平均划分为AD的“高风险和低风险”(HR&LR)，定义为具有遗传风险和 CMD与那些没有的。目前，我们正在招聘100人(年龄在50-70岁之间)，我们将在 目前的研究年龄为55-75岁。我们将开发一个通用的AD多基因风险评分(PRS)和一个性别分层的PR 选择HR和LR以及有无CMD的个体。我们正在进行广泛的门诊 结构和功能磁共振成像(S/功能磁共振成像)、认知功能、激素和免疫的评估 概况、心脏生理学、神经血管结构/功能、基因、RNA转录和细胞代谢 单核细胞、Aβ正电子发射计算机断层扫描和AD血液生物标记物。在这里，我们建议再招聘一名 140名HR和LR受试者，按性别平均分配，以便获得足够的统计能力来测试 共同的性别依赖的影响，免疫失调的基础上的CMD和AD的联系- 相关病理学。此外，我们将跟踪目前的100名受试者来评估免疫的纵向影响 性别对AD相关病理5年变化的失调。我们预测，HR与LR的个人将 表现出显著更强的AD相关病理[基于血液和PET的AD生物标志物和记忆电路 内嗅皮层、顶叶、扣带回、内侧前额叶皮质、蓝斑和 下丘脑室旁核]、代谢和神经血管缺陷以及免疫调节失调 绝经后妇女的途径基因、细胞代谢和增加的促炎标记物 比男人还糟。此外，我们预测免疫失调将中介(即，部分解释)这种关系 HR与LR和AD相关病理之间的关系，这种中介作用将更强(影响范围更大) 绝经后女性与男性的对比。最后，在探索性分析中，我们预测CMD的存在将 加剧遗传风险对AD相关病理的影响，女性经历更严重 结果比男人更重要。总体而言，识别性别依赖机制将对 开发神经免疫疗法，这种疗法可能因性别而异，并及早针对预防。

Summary By 2050, approximately 13.8 million people in the U.S. are projected to have Alzheimer's disease (AD), two- thirds of whom will be women. Secondary to genetics, cardiometabolic diseases (CMD), such as hypertension and diabetes, are major independent risk factors for AD. There are significant sex differences in pathology, timing, and clinical presentation of these diseases in early midlife. Despite this, the shared pathophysiology underlying CMD and AD, and sex differences therein, are largely unexplored. Here, we will test the hypothesis that sex differences in immune pathophysiology, in part, underlies the sex-dependent impact of cardiometabolic dysfunction on AD risk in midlife. We propose to recruit 240 people, ages 50- 75, equally divided by sex, that are “high and low risk” (HR & LR) for AD, defined as those with genetic risk and CMD vs. those without. Currently, we are recruiting 100 people (ages 50-70), whom we will re-recruit in the current study at ages 55-75. We will develop a general AD polygenic risk score (PRS) and a sex-stratified PRS to select HR and LR individuals along with presence or absence of CMD. We are conducting extensive in-clinic assessments to characterize structural and functional MRI (s/fMRI), cognitive function, hormone and immune profiling, cardiophysiology, neurovascular structure/function, genotype, RNA transcription and cell metabolism of monocyte cells, Aβ PET imaging, and AD blood-based biomarkers. Here, we propose to recruit an additional 140 HR and LR subjects, equally divided by sex, in order to obtain adequate statistical power to test for the shared sex-dependent impact of immune dysregulation underlying the association between CMD and AD- related pathology. Further, we will follow the current 100 subjects to evaluate the longitudinal impact of immune dysregulation on 5-year change in AD-related pathology by sex. We predict that HR vs. LR individuals will express significantly greater AD-related pathology [blood-based & PET AD biomarkers and memory circuitry deficits in entorhinal cortex, temporoparietal, cingulate, medial prefrontal cortex, locus coeruleus, and paraventricular hypothalamic nucleus], metabolic and neurovascular deficits, and dysregulation of immune pathway genes, cellular metabolism, and increased pro-inflammatory markers, with postmenopausal women worse than men. Further, we predict immune dysregulation will mediate (i.e., in part, explain) the relationship between HR vs. LR and AD-related pathology, and that this mediation will be stronger (larger effect sizes) in postmenopausal women versus men. Finally, in exploratory analyses, we predict that the presence of CMD will exacerbate the effects of genetic risk alone on AD-related pathology, with women experiencing worse outcomes than men. Overall, identifying sex-dependent mechanisms will have substantial implications for developing neuroimmune therapeutics that may differ by sex and targeted early for prevention.