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

项目总结/摘要 我们建议的项目重点是了解性别和性别对生物过程的互动影响 与阿尔茨海默病（AD）风险有关。性别被定义为一个人表现为女性或男性， 性别是由染色体和性器官决定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，是否暴露于性别相关的压力与神经和外周过程，促进 AD病理学，或者性激素是否介导这些关系，是未知的。在本建议中，我们力求 了解与性别相关的压力暴露和雌激素水平对记忆的交互作用，记忆- 相关的神经激活、静息时的功能连接（FC）和外周炎症。这样做 该提案有助于进一步研究AD机制和开发干预措施以降低AD风险。的 本提案的目的是确定与性别有关的终生压力源暴露的交互影响， 雌激素水平对记忆相关脑激活、静息状态FC、外周炎症和言语功能的影响 由于家族史而有AD风险的中年女性的记忆力。该项目的理由是， 以应激暴露和雌激素为指标的性别，交互促进神经激活、FC和 外周炎症，这可能会促进处于AD风险中的女性的AD病理学。具体目标1将调查 性别相关应激暴露和雌激素水平对记忆过程中fMRI激活的交互作用 编码、fMRI任务性能和静态默认模式网络（DMN）FC。第2章调查 与性别相关的应激源暴露和雌激素交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时fMRI激活和FC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，该诊所为因家族史而有AD风险的女性提供服务。具体目标1-2将包括寿命 性别相关的压力暴露作为预测因子，作为结果，模式分离功能磁共振成像任务，静息状态 扫描，促炎细胞因子的血浆水平，以及非文字记忆的神经心理学测量。具体 AIM 3将使用促炎细胞因子的血浆水平作为基于任务的激活和静息的预测因子 州FC。所有分析将包括雌二醇水平作为介质。这项研究有望提供证据 在有AD风险的女性中，将更大的终生性别相关压力源暴露与更差的文字记忆相关， 以及可能导致AD中性别差异的过程，如海马过度激活 在记忆编码过程中，DMN失活减少，静息时后DMN FC大于前DMN FC， 外周炎症更严重。拟议的研究在关注受性别影响的变量方面具有创新性 和性别，可能催化AD风险女性的AD病理学，并在提供强有力的 为进一步研究炎症和神经活动以及FC作为AD机制提供了科学依据。结果 我们的研究将为开发针对压力和炎症的干预措施以降低AD风险提供信息。

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.