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

免疫功能性别差异对心脏代谢疾病共同风险的影响

• 批准号: 10300822
• 负责人: JILL M GOLDSTEIN
• 金额: $ 378.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300822
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Attenuated; Biological Markers; Blood; Blood Circulation; Brain; Brain region; Cardiometabolic Disease; Cardiovascular alteration; Cells; Cellular Metabolic Process; Chronic; Clinic; Clinical; DNA Library; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Early Intervention; Electronic Health Record; Etiology; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Genetic Risk; Genetic Transcription; Genotype; High Prevalence; Hormones; Hypertension; Immune; Immune System Diseases; Individual; Inflammation; Inflammatory; Lead; Medial; Mediating; Mediation; Memory; Metabolic; Metabolism; Methods; Mitochondria; Neuroimmune; Outcome; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Positron-Emission Tomography; Postmenopause; Prefrontal Cortex; Prevention; Public Health; RNA; Reporting; Research; Respiration; Sample Size; Secondary to; Sex Differences; Structure; Testing; Therapeutic; Time; Vascular Diseases; Visit; Woman; amyloid pathology; base; biobank; blood-based biomarker; burden of illness; cardiometabolism; cognitive function; disorder risk; entorhinal cortex; experience; fetal; immune function; inflammatory marker; insight; locus ceruleus structure; men; middle age; mild cognitive impairment; monocyte; neuroinflammation; neurovascular; paraventricular nucleus; polygenic risk score; pre-clinical; prevent; protein biomarkers; recruit; response; risk sharing; sex; sexual dimorphism

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.

总结 到2050年，预计美国约有1380万人患有阿尔茨海默病（AD），其中20%为老年痴呆症。 其中三分之一是女性。继发于遗传、心脏代谢疾病（CMD），如高血压 和糖尿病是AD的主要独立危险因素。在病理学上有显著的性别差异， 这些疾病在中年早期的时间和临床表现。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未被探索。在这里，我们将测试 假设免疫病理生理学中的性别差异，部分是性别依赖性的基础， 心脏代谢功能障碍对中年AD风险影响我们计划招募240人，年龄50- 75人，按性别平均划分，这些人是AD的“高风险和低风险”（HR & LR），定义为具有遗传风险的人， CMD与那些没有。目前，我们正在招募100名员工（年龄在50-70岁之间），我们将在 目前的研究年龄在55-75岁之间。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PRS 选择HR和LR个体沿着CMD的存在或不存在。我们正在进行广泛的诊所内 评估以表征结构和功能MRI（s/fMRI）、认知功能、激素和免疫 分析、心脏生理学、神经血管结构/功能、基因型、RNA转录和细胞代谢 单核细胞、Aβ PET成像和AD血液生物标志物。在此，我们建议增聘一名 140名HR和LR受试者，按性别平均分配，以获得足够的统计功效来检验 共同的免疫失调的性别依赖性影响是CMD和AD之间关联的基础， 相关病理学此外，我们将跟踪目前的100名受试者，以评估免疫的纵向影响。 按性别列出的AD相关病理学的5年变化失调。我们预测HR与LR个体将 表达显著更大的AD相关病理[血液和PET AD生物标志物和记忆回路 内嗅皮层、颞顶、扣带回、内侧前额叶皮层、蓝斑和 下丘脑室旁核]、代谢和神经血管缺陷以及免疫调节障碍 通路基因、细胞代谢和促炎标志物增加与绝经后妇女 比男人更坏。此外，我们预测免疫失调将介导（即，部分解释）关系 HR vs. LR和AD相关病理之间的关系，并且这种介导作用在以下情况下更强（效应量更大）： 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 加剧了遗传风险对AD相关病理学的影响， 结果比男人。总的来说，确定性别依赖机制将对以下方面产生重大影响： 开发可能因性别而异的神经免疫疗法，并及早预防。