Sex Differences in the Clinical Expression of Alzheimer's Disease Neuropathology and Their Underlying Biological Mechanisms

项目总结/摘要 阿尔茨海默病（AD）风险和AD病理负担的性别差异已被证实。 广泛研究;然而，很少有人知道AD病理负担如何与临床症状相关， 女人对男人AD临床前阶段认知优势的证据，但两倍陡峭 认知能力下降表明，AD临床表现的性别差异问题 病理学是很重要的一个。这些性别差异具有临床意义，因为我们已经建立了 通常生成用于诊断和跟踪疾病的AD临床和生物标志物的阈值 不考虑性别差异。如果女性能够更好地保持我们目前的认知， 阈值考虑“正常”认知，直到比男性更高级的病理状态，然后诊断为MCI 可能会延迟，从而限制了早期干预的机会。我们假设，性别差异，在 AD病理学的临床转化来自于脑相关弹性/风险因素的性别特异性平衡 随着疾病的发展而改变我们的建议特别具有创新性，因为我们将首先描述性 AD病理学如何与疾病阶段的临床症状相关的差异，然后检查其 神经生物学基础和临床意义。 我们将利用来自阿尔茨海默病神经成像的体内纵向生物标志物数据， 主动（ADNI）和前瞻性神经病理学数据在脑组织从多种阿尔茨海默病 研究中心（ADRC）。考虑到他们与AD病理学的紧密联系以及我们早期研究发现的性别差异， 数据显示，我们将研究脑弹性/风险机制（1）PET测量的脑葡萄糖 代谢，（2）NMDAR密度，谷氨酸神经传递的标志物，和（3）转运蛋白18 kDA （TSPO）水平，小胶质细胞活化的标志物。具体而言，目标1将利用ADNI数据来检查性别 认知功能轨迹的差异及其与AD病理学纵向变化的关系 （Aβ和Tau）和脑代谢。在目标2中，我们将进行体外放射自显影， 正常对照组、轻度认知障碍组和AD痴呆组各60例 尸检病例，以确定斑块、缠结、NMDAR和TSPO密度的性别差异及其相关性 以及三个诊断组中每一个的死前认知功能。在目标3中，我们 针对这些性别差异采取行动，为认知测试生成性别特异性分数， MCI/AD诊断标准，在检测是否存在 AD生物标志物/病理学的临床显著水平。我们项目的公共卫生效益将是 重要的是，通过理解和解释我们临床和生物标志物方法中的性别差异， 到AD诊断，我们将改善疾病诊断和跟踪的临床和生物标志物方法， 性别，并可能确定性别特异性治疗靶点。

PROJECT SUMMARY/ABSTRACT Sex differences in the risk of Alzheimer’s disease (AD) and AD pathology burden have been extensively studied; however, little is known about how AD pathology burden relates to clinical symptoms in women versus men. Evidence of a cognitive advantage in the preclinical stage of AD, yet a two-times steeper cognitive decline thereafter indicate that the question of sex differences in the clinical manifestation of AD pathology is an important one. These sex differences have clinical implications in that our established thresholds for AD clinical and biological markers used to diagnose and track disease were typically generated without consideration for sex disparities. If women are better able to maintain what our current cognitive thresholds consider “normal” cognition until a more advanced pathology state than men, then diagnosis of MCI could be delayed, thus limiting the opportunity for early intervention. We hypothesize that sex differences in the clinical translation of AD pathology results from a sex-specific balance of brain-related resilience/risk factors that change with disease stage. Our proposal is particularly innovative in that we will first characterize sex differences in how AD pathology relates to clinical symptoms by disease stage and then examine its neurobiological underpinnings and clinical implications. We will leverage both in-vivo, longitudinal biomarker data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and prospective neuropathological data in brain tissue from multiple Alzheimer’s Disease Research Centers (ADRCs). Given their strong ties to AD pathology and the sex differences that our earlier data show, we will examine the brain resilience/risk mechanisms of (1) PET-measured brain glucose metabolism, (2) NMDAR density, a marker of glutamate neurotransmission, and (3) translocator protein 18kDA (TSPO) levels, a marker of microglial activation. Specifically, Aim 1 will utilize ADNI data to examine sex differences in trajectories of cognitive function and their relationship to longitudinal variation in AD pathology (Aβ and Tau) and brain metabolism by AD stage. In Aim 2, we will conduct in vitro autoradiography in hippocampal and cortical brain tissue of 60 normal control, 60 mild cognitive impairment and 60 AD dementia autopsy cases to determine sex differences in plaque, tangle, NMDAR and TSPO density and how they relate to each other and to antemortem cognitive function in each of the three diagnostic groups. In Aim 3, we will take action on these sex differences by generating sex-specific cut-scores for cognitive tests commonly used in MCI/AD diagnostic criteria with the optimal balance of sensitivity/specificity in detecting the presence of clinically-significant levels of AD biomarkers/pathology. The public health benefits of our project would be significant in that by understanding and accounting for sex disparities in our clinical and biomarker approaches to AD diagnosis, we will improve clinical and biomarker approaches to disease diagnosis and tracking in both sexes and possibly identify sex-specific therapeutic targets.