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，女性表现出更大的认知能力下降，并且受到年龄相关因素的影响更严重 疾病（例如，阿尔茨海默病（AD））。AD风险因素的影响，如载脂蛋白E4（ApoE4） 等位基因，AD生物标志物的积累和AD的认知障碍在女性中更明显， 并不仅仅反映了它们更长寿。这些性别差异的原因尚不清楚，因此， 重要的是探索老化大脑中性别差异的生物学基础。更年期可能有助于 老龄化对女性的不成比例的影响，因为它伴随着雌激素的大量减少， 对大脑健康和认知有神经保护作用。值得注意的是，AD病理学开始发展几十年， 在临床症状发作之前，AD的这个临床前阶段与绝经过渡期重叠， 中年（40年代末至50年代初）。因此，绝经期雌激素的消耗可能会增加女性的易感性 AD的发病机制。事实上，生殖激素的变化与以下疾病的风险增加有关： 发展为AD和记忆功能差。内侧颞叶（MTL）网络，这是重要的， 记忆，在衰老和AD中功能失调。更年期妇女的情感记忆缺陷 AD病理学的转变和早期发展。此外，情绪记忆大脑网络的早期变化， 包括MTL，已经在临床前AD中被发现，并且是第一个积累AD病理学的。给定 绝经和早期AD之间相互作用的大量证据，询问 生殖衰老和AD风险对于揭示年龄相关疾病中涉及的性别特异性因素至关重要， 创造新的治疗或预防方法。然而，更年期对衰老的影响 女性缺乏，特别是在AD遗传风险的背景下。为了弥补这些差距，拟议项目 将研究绝经后雌激素下降对MTL网络动力学和情绪记忆的影响 在有AD风险的认知正常女性中（例如，ApoE 4+）。目的1将建立雌激素与 Aim 2将量化雌激素对MTL网络连接性的影响， Aim 3将确定雌激素对MTL激活和情绪的影响， 有AD风险的女性的记忆力。总之，拟议的工作将提供重要的新的见解， AD性别差异的生物学机制研究更年期对认知能力的影响 在AD病理学开始的同一时间段内的正常衰老可以提供一种新的方法， 早期发现AD。这些目标将为申请人提供许多培训机会， 在复杂的神经成像分析，增强统计技能，衰老研究对疾病的应用 状态（例如，，以及宝贵的指导经验。这项工作提供的培训机会将 加速申请人向独立职业的过渡，重点关注老龄化结果的性别差异。