Interactions of Sex and Gender Factors in Risk for Alzheimers Disease: Links Between Stress, Neural Activity, Inflammation, and Memory

项目摘要/摘要 我们建议的项目侧重于了解性别和性别对生物过程的交互影响 与阿尔茨海默病(AD)风险有关。性别被定义为个体的表现为女性或男性， 而性别是由染色体和性器官定义的。压力既有与性别有关的成分，也有与性别有关的成分。 然而，暴露于与性别相关的压力源是否与促进 AD病理，或者说性激素是否调节这些关系，目前尚不清楚。在这项建议中，我们寻求 了解与性别相关的压力源暴露和雌激素水平对记忆的交互影响 相关的神经激活、静息功能连接(FC)和外周炎症。在这样做的时候， 该提案使进一步研究AD机制和制定干预措施降低AD风险成为可能。这个 这项建议的目的是确定与性别相关的终生应激源暴露和 雌激素水平对记忆相关脑激活、静息状态Fc、外周炎症和言语的影响 中年妇女的记忆由于家族史而有患AD的风险。这个项目的基本原理是性别和 以压力暴露和雌激素为指标的性行为，交互地促进神经激活、Fc和 外周炎症，这可能促进有AD风险的女性的AD病理。特定目标1将调查 性别相关应激源暴露和雌激素水平对记忆中fMRI激活的交互作用 静态编码、fMRI任务性能和默认模式网络(DMN)FC。《特定目标2》将展开调查 性别相关应激源暴露和雌激素相互作用对外周炎症和言语的影响 记忆。具体目标3将研究外周炎症对静息状态下fMRI激活和功能障碍的影响。 为了实现这些目标，我们将从我们的妇女阿尔茨海默氏症运动预防中心招募参与者 在克利夫兰诊所，该诊所为因家族病史而有AD风险的女性提供服务。具体目标1-2将包括终生目标 与性别相关的压力源暴露作为预测因素，作为结果，模式分离功能磁共振任务，休息状态 扫描，血浆促炎细胞因子水平，以及言语记忆的神经心理测量。特定的 目标3将使用血浆促炎细胞因子水平作为基于任务的激活和休息的预测因子 州本币。所有的分析都将包括雌二醇水平作为中介。这项研究有望提供证据 阿尔茨海默病风险女性一生中较大的性别相关应激源暴露与较差的言语记忆之间的关系，AS 以及可能导致阿尔茨海默病性别和性别差异的过程，如海马区过度激活 减少了记忆编码期间DMN的失活，在静止时更大地位于前DMN FC之后，以及 外周炎症程度较高。这项拟议的研究在关注性别影响的变量方面具有创新性。 和性别，这可能会催化AD高危女性的AD病理，并在提供强大的 进一步研究炎症和神经活动以及FC作为AD机制的科学依据。结果： 我们的研究将为针对应激和炎症的干预措施的发展提供信息，以降低AD风险。

PROJECT SUMMARY/ABSTRACT Our proposed project focuses on understanding interactive effects of gender and sex on biological processes implicated in Alzheimer’s disease (AD) risk. Gender is defined as an individual’s presentation as female or male, and sex is defined by chromosomes and sex organs. Stress has both gender- and sex-linked components. However, whether exposure to gender-linked stressors relates to neural and peripheral processes that promote AD pathology, or whether sex hormones mediate these relationships, is unknown. In this proposal, we seek to understand interactive effects of gender-linked stressor exposure and estrogen levels on memory, memory- related neural activation, functional connectivity (FC) at rest, and peripheral inflammation. In doing so, the proposal enables further study of AD mechanisms and development of interventions to reduce AD risk. The objective of this proposal is to determine interactive effects of lifetime gender-linked stressor exposure and estrogen levels on memory-related brain activation, resting state FC, peripheral inflammation, and verbal memory in midlife women at risk for AD due to family history. The rationale for this project is that gender and sex, indexed by stress exposures and estrogen, interactively promote changes in neural activation, FC, and peripheral inflammation, which may facilitate AD pathology in women at risk for AD. Specific Aim 1 will investigate interactive effects of gender-linked stressor exposure and estrogen levels on fMRI activation during memory encoding, fMRI task performance, and default mode network (DMN) FC at rest. Specific Aim 2 will investigate effects of gender-linked stressor exposure and estrogen interactivity on peripheral inflammation and verbal memory. Specific Aim 3 will investigate the effects of peripheral inflammation on fMRI activation and FC at rest. To achieve these aims, we will recruit participants from our Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic, which serves women at risk for AD due to family history. Specific Aims 1-2 will include lifetime gender-linked stressor exposure as a predictor, and as outcomes, a pattern separation fMRI task, a resting state scan, plasma levels of pro-inflammatory cytokines, and neuropsychological measures of verbal memory. Specific Aim 3 will use plasma levels of pro-inflammatory cytokines as predictors of task-based activation and resting state FC. All analyses will include estradiol levels as a mediator. This study is expected to provide evidence relating greater lifetime gender-linked stressor exposures to poorer verbal memory in women at risk for AD, as well as to processes likely to contribute to sex and gender disparities in AD, such as hippocampal hyperactivation and reduced DMN deactivation during memory encoding, greater posterior to anterior DMN FC at rest, and higher peripheral inflammation. The proposed research is innovative in its focus on variables impacted by sex and gender that may catalyze AD pathology in women at risk for AD, and is significant in providing strong scientific justification for further study of inflammation and neural activity and FC as AD mechanisms. Results of our study will inform development of interventions targeting stress and inflammation to reduce AD risk.