Estrogen Declines with Menopause: Impacts on the Medial Temporal Lobe Network and Emotional Memory in Aging Females at Genetic Risk for Alzheimer’s Disease

雌激素随更年期下降：对有阿尔茨海默病遗传风险的老年女性内侧颞叶网络和情绪记忆的影响

• 批准号: 10607612
• 负责人: Hannah Ballard
• 金额: $ 7.32万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-16 至 2026-03-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607612
• 关键词: Abeta clearance; Acceleration; Address; Adult; Age; Aging; Alleles; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amenorrhea; Apolipoproteins; Atrophic; Behavior; Behavioral; Biological; Brain; Clinical; Cognition; Cognitive; Complex; Data; Development; Discrimination; Disease; Disease Progression; Disparate; Early Diagnosis; Elderly; Emotional; Endocrine; Estradiol; Estrogen decline; Estrogens; Exhibits; Female; Genetic Risk; Gonadal Steroid Hormones; Health; Hippocampus; Hyperactivity; Impaired cognition; Intervention; Longevity; Magnetic Resonance Imaging; Measures; Medial; Mediating; Memory; Menopause; Menstrual cycle; Mentorship; Methods; Neurobiology; Neurosecretory Systems; Outcome; Pathogenesis; Pathology; Performance; Perimenopause; Phase; Postmenopause; Predisposition; Premenopause; Prevention; Process; Research; Resolution; Rest; Risk; Risk Factors; Sex Differences; Signal Transduction; Stimulus; Symptoms; Temporal Lobe; Therapy trial; Time; Work; age related; aging brain; apolipoprotein E-4; brain health; career; cognitive performance; endophenotype; experience; functional MRI scan; genetic risk factor; healthy aging; hormone therapy; innovation; insight; male; middle age; neuroimaging; neuroprotection; normal aging; novel strategies; pre-clinical; reproductive; reproductive hormone; reproductive senescence; salivary assay; sex; skills; support network; training opportunity

Project Summary Relative to males, females exhibit greater cognitive decline and are more severely impacted by age-related disease (e.g., Alzheimer’s disease (AD)). The impact of AD risk factors such as the apolipoprotein E4 (ApoE4) allele, accumulation of AD biomarkers, and cognitive impairment with AD is more pronounced in females and does not simply reflect their greater longevity. The reasons for these sex differences remains unclear, thus, it is important to probe the biological underpinnings of sex distinctions in the aging brain. Menopause may contribute to the disproportionate impact of aging on females as it is accompanied by a large decrease in estrogens, which have neuroprotective effects on brain health and cognition. Notably, AD pathology begins to develop decades before clinical symptom onset, and this preclinical phase of AD overlaps with the menopausal transition during mid-life (late 40s-early 50s). Thus, the depletion of estrogen with menopause may increase female susceptibility to AD pathogenesis. In fact, changes in reproductive hormones have been associated with increased risk for developing AD and poor memory function. The medial temporal lobe (MTL) network, which is important for memory, is dysfunctional in aging and AD. Deficits in emotional memory are observed with the menopausal transition and early development of AD pathology. Moreover, early changes in emotional memory brain networks, including the MTL, have been discovered in preclinical AD and are the first to accumulate AD pathology. Given substantial evidence of interactions between menopause and early AD, interrogating the linkage between reproductive aging and AD risk is critical for uncovering sex-specific factors involved in age-related disease and creating novel approaches to treatment or prevention. However, work on the impact of menopause in aging females is lacking, especially in the context of genetic risk for AD. To address these gaps, the proposed project will examine the effect of estrogen decline with menopause on MTL network dynamics and emotional memory in cognitively normal females at risk for AD (e.g., ApoE4+). Aim 1 will establish the relationship between estrogen levels and AD risk in aging females, Aim 2 will quantify the impact of estrogen on MTL network connectivity in aging females at risk for AD, and Aim 3 will determine the effect of estrogen on MTL activation and emotional memory in females at risk for AD. Together, the proposed work will provide important new insight into the biological mechanisms underlying sex differences in AD. Examining the impact of menopause in cognitively normal aging during the same timeframe that AD pathology begins could provide a novel approach towards the early detection of AD. These aims will offer many training opportunities for the applicant, who will gain proficiency in complex neuroimaging analyses, enhanced statistical skills, application of aging research towards disease states (e.g., AD), and valuable mentorship experience. The training opportunities facilitated by this work will accelerate the applicant’s transition to an independent career focused on sex differences in aging outcomes.

项目摘要 相对于男性，女性暴露了更大的认知能力下降，并受到年龄相关的严重影响 疾病（例如，阿尔茨海默氏病（AD））。 AD危险因素（例如载脂蛋白E4（APOE4））的影响 等位基因，AD生物标志物的积累以及AD的认知障碍在女性中更为明显 不仅反映了他们更长的寿命。这些性别差异的原因尚不清楚，因此， 探测衰老大脑中性别区别的生物学基础很重要。更年期可能会做出贡献 衰老对女性的影响不成比例的影响，伴随着雌激素的大幅度降低，这 对脑健康和认知具有神经保护作用。值得注意的是，广告病理开始发展数十年 在临床症状发作之前，以及AD的临床前阶段与更年期过渡重叠 中年（40年代末50年代后期）。那就是雌激素对更年期的耗竭可能会增加女性的敏感性 进行AD发病机理。实际上，生殖激素的变化与增加的风险有关 开发AD和不良记忆功能。中位临时叶（MTL）网络，这对于 记忆，在衰老和AD中功能失调。在绝经中观察到情绪记忆的不足 AD病理的过渡和早期发展。此外，情绪记忆大脑网络的早期变化， 包括MTL在内，已在临床前AD中发现，并且是第一个积累AD病理学的人。给出 更年期和早期广告之间相互作用的实质证据，询问 生殖衰老和AD风险对于发现与年龄相关疾病的性别特异性因素至关重要 创建新颖的治疗或预防方法。但是，致力于更年期在衰老中的影响 缺乏女性，尤其是在AD遗传风险的情况下。为了解决这些差距，拟议的项目 将检查雌激素下降的影响，而更年期对MTL网络动态和情感记忆 在认知正常的女性中，AD风险（例如APOE4+）。 AIM 1将建立雌激素之间的关系 AIM 2在衰老女性中的水平和AD风险将量化雌激素对MTL网络连接的影响 衰老的女性有AD的风险，AIM 3将决定雌激素对MTL激活和情绪的影响 女性的记忆风险有AD。拟议的工作将共同提供有关该研究的重要新见解 AD中性别差异的生物学机制。检查更年期在认知上的影响 在同一时间范围内，AD病理学可以为该方法提供一种新颖的方法 早期发现AD。这些目标将为申请人提供许多培训机会，他们将获得熟练程度 在复杂的神经影像学分析中，统计技能增强，对疾病的衰老研究应用 国家（例如AD）和宝贵的精神经验。这项工作准备的培训机会将 加速申请人向独立职业的过渡，专注于衰老成果的性别差异。