Biological and lifestyle factors contributing to Tau in women at risk for Alzheimer's disease.

项目摘要/摘要越来越多的证据报告表明，女性对 阿尔茨海默病(AD)比病理性tau负担更大、认知能力下降更严重的男性更多；然而 人们对这些性别差异的原因知之甚少。阿尔茨海默病的性别差异指向不同性别的原因 途径以及针对性别的治疗靶点。神经炎症(N-inf)是一种候选的偶然途径 这表明了性别差异，并在AD发病机制中发挥着核心作用，与tau和认知都有密切联系 拒绝。女性往往有更强大的免疫/炎症反应，占自身免疫的80% 疾病病例。此外，我们自己在阿尔茨海默病神经成像倡议中的初步工作表明 女性可能比男性更容易受到N-Inf的不良影响，特别是肿瘤坏死因子α的标记物， IL6及其受体对脑脊液中磷酸化tau(p-tau)水平和认知功能的影响。 还有一些生活方式因素，如体力活动和阻塞性睡眠呼吸暂停(OSA)，已知会影响N- 并与tau和认知能力下降有关，并且在女性和男性中的作用是不同的。我们自己的初步数据 强调久坐行为和阻塞性睡眠呼吸暂停是两个可改变的危险因素，表现出强烈的 与老年妇女的N-inf、tau和/或认知功能的关系，因此强调有必要进一步 了解这些生活方式干预如何以及在多大程度上可以降低AD风险。总而言之，这些发现 这项拟议的观察性研究将检验N-inf标志物(特别是肿瘤坏死因子α、肿瘤坏死因子2、白介素6 和IL6R)，而影响N-inf的可改变的危险因素与tau的积累和认知能力下降有关。 老年妇女有轻微的认知缺陷和遗传风险，有患AD的风险。此外，我们还将探索性是如何 荷尔蒙，特别是睾丸激素，由于其抗炎和中枢作用，对这些关系起到了作用。 神经系统的影响，常常是导致性别差异的原因。为了实现这一目标，我们建议采取措施 100例高危老年妇女的脑脊液N-inf标志物、体力活动、OSA和循环性激素 并将这些测量与认知功能的变化和tau的积累联系起来，通过 正电子发射断层扫描(PET)，为期两年。这项研究将建立在一个国家资助的试点项目上 研究通过增加样本量和增加纵向评估来进行严谨的 检验我们的假设。为了与NIH的研究优先事项保持一致，在5年的潜在资金之后，这 该项目将帮助弥合我们对阿尔茨海默病性别差异的理解方面的关键差距，通过审查未被充分探索的 然而，高度相关的机制可能有助于更大的病理和更陡峭的认知能力下降 公元后轨道上的女性。此外，我们的发现将为影响这些因素的风险降低策略提供参考。 机制--鉴于目前缺乏改善疾病的治疗方法，这是一个重要的重点。

PROJECT SUMMARY/ABSTRACT Growing evidence reports that women show a more aggressive profile of Alzheimer's disease (AD) than men with greater pathological tau burden and steeper cognitive decline; yet the reasons for these sex differences are poorly understood. Sex differences in AD point to sex-disparate causal pathways as well as sex-specific therapeutic targets. Neuroinflammation (N-Inf) is one candidate casual pathway that shows sex disparities and plays a central role in AD pathogenesis with close ties to both tau and cognitive decline. Women tend to have a more robust immune/inflammatory response and comprise 80% of autoimmune disease cases. Moreover, our own preliminary work in the Alzheimer's Disease Neuroimaging Initiative indicated that women may be more susceptible than men to the adverse effect of N-Inf, particularly the markers of TNFα, IL6 and their receptors on cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and cognitive function. There are also lifestyle factors such as physical activity and obstructive sleep apnea (OSA) known to influence N- Inf and relate to tau and cognitive decline and to do so differently in women versus men. Our own preliminary data highlight sedentary behavior and obstructive sleep apnea as two modifiable risk factors that show strong associations with N-Inf, tau and/or cognitive function in older women, and thus stress the need to further understand how and to what degree these lifestyle interventions could reduce AD risk. Together, these findings led us to this proposed observational study that will examine how N-Inf markers (specifically TNFα, TNFR2, IL6 and IL6R) and the modifiable risk factors that influence N-Inf relate to tau accumulation and cognitive decline in older women at-risk for AD by way of mild cognitive deficits and genetic risk. Moreover, we will explore how sex hormones, particularly testosterone, contribute to these relationships given their anti-inflammatory and central nervous system effects and often contributing role to sex differences. To achieve this, we propose to measure CSF N-Inf markers, physical activity, OSA, and circulating sex hormones in a sample of 100 older women at-risk for AD and relate these measures to changes in cognitive function and accumulation of tau, measured via positron emission tomography (PET), over a two-year period. This study will build upon a state-funded, pilot study by increasing the sample size and adding longitudinal assessments in order to conduct a rigorous examination of our hypotheses. In keeping with NIH research priorities, after 5 years of potential funding, this project will help to close critical gaps in our understanding of sex differences in AD by examining under-explored yet highly-relevant mechanisms that may contribute to the greater pathology and steeper cognitive decline in women on the AD trajectory. Furthermore, our findings will inform risk reduction strategies that influence these mechanisms – an important focus given current the lack of disease-modifying treatments.