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

项目摘要 相对于男性，女性表现出更大的认知衰退，并且受年龄相关的影响更严重 疾病(例如阿尔茨海默病(AD))。载脂蛋白E4(ApoE4)等AD危险因素的影响 等位基因、AD生物标记物的积累以及与AD有关的认知障碍在女性和 并不仅仅反映出它们更长寿。造成这些性别差异的原因尚不清楚，因此， 重要的是要探索老化大脑中性别差异的生物学基础。更年期可能起到一定作用 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幅下降，这 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 在临床症状出现之前，AD的这一临床前阶段与绝经期间的过渡重叠 中年(40岁末-50岁出头)。因此，绝经后雌激素的耗竭可能会增加女性的易感性。 对AD发病机制的影响。事实上，生殖荷尔蒙的变化与罹患癌症的风险增加有关 发展中的AD和较差的记忆功能。内侧颞叶(MTL)网络，这是重要的 记忆，在衰老和阿尔茨海默病中功能失调。情绪记忆的缺陷是在绝经期观察到的。 阿尔茨海默病病理学的变迁和早期发展。此外，情绪记忆大脑网络的早期变化， 包括MTL，已在临床前AD中被发现，并最先积累了AD的病理。vt.给出 更年期和早期AD之间相互作用的大量证据，质疑两者之间的联系 生殖老龄化和AD风险对于揭示与年龄相关的疾病和 创造新的治疗或预防方法。然而，关于更年期对衰老的影响的研究 缺乏女性，特别是在阿尔茨海默病遗传风险的背景下。为了弥补这些差距，拟议的项目 我将研究绝经后雌激素水平下降对MTL网络动力学和情绪记忆的影响 有AD风险的认知正常女性(例如，载脂蛋白E4+)。目标1将建立雌激素与 老年女性的水平和AD风险，目标2将量化雌激素对MTL网络连接的影响 老年女性面临阿尔茨海默病的风险，目标3将确定雌激素对MTL激活和情绪的影响 患阿尔茨海默病的女性的记忆。总之，拟议的工作将为我们提供对 阿尔茨海默病性别差异的生物学机制。从认知角度审视更年期的影响 在AD病理开始的同一时间段内正常衰老可能提供一种新的方法 早期发现阿尔茨海默病。这些目标将为申请者提供许多培训机会，他们将获得熟练的技能 在复杂的神经成像分析中，增强了统计技能，将老龄化研究应用于疾病 国家(例如AD)，以及宝贵的指导经验。这项工作带来的培训机会将 加快申请者向专注于年龄结果性别差异的独立职业的过渡。

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.