Sex differences in the progression of Alzheimer's disease: is menopause the key?

项目摘要 这项拟议研究的总体目标是阐明可能增加 女性易患阿尔茨海默病（AD）相关的认知能力下降，使用最先进的多模式 神经影像学，在中年和老年人。据报道，女性经常表现出更高的 临床进展为AD痴呆的患者多于男性。然而，申请人的初步数据表明， 淀粉样蛋白负荷存在最小的性别差异，这意味着其他病理生理机制，如tau， 可能会影响老年女性认知能力下降的后续风险增加。同样重要的是要调查 在中年期间AD生物标志物积累的性别差异早期出现，当性别和激素 这些因素可能会产生特殊的影响。在K99阶段，第一个目标将确定AD的性别差异 临床正常老年人中淀粉样蛋白、tau和神经变性的神经成像生物标志物。第二 目的是确定性别和基线AD生物标志物之间的关系， 在同一个样本中下降。基于初步数据的主要假设是， 显示出更大的tau负担，神经退行性变和认知下降率，尽管水平相似， 淀粉样蛋白负荷，可能是由于性别和APOE基因型之间的相互作用。为了实现这些目标， 申请人将利用现有的统计建模和认知神经科学的优势，获得专业知识， 培训的四个关键领域：（1）多模态成像，（2）数据协调，（3）纵向建模，以及（4） 性生物学随着这些技能的发展，申请人将在R 00阶段处于有利地位， 最终目的：研究中年人AD生物标志物积累的性别差异。在 此外，候选人将侧重于激素阶段（绝经前，围绝经期， 绝经）对AD生物标志物积累率的影响。一个高度创新 该项目的组成部分是使用多模式神经成像（正电子发射断层扫描（PET）和 磁共振成像）和遗传学，以了解机制的基础更大的女性风险， AD.这项拟议的研究将提供一些关于区域tau-PET负荷性别差异的初步见解。 中老年人的临床前AD。提高K99中检测性别效应的统计功效 在第一阶段，数据将在三个特征良好的纵向老年人队列（60-90岁）中进行协调 年）。对于R 00阶段，将采用类似的方法来协调三个纵向 中年人（40-65岁）。阐明性别特异性对阿尔茨海默病（AD）风险的影响 对理解催化癌症的生物机制有着深远的影响。 AD风险，并更好地支持临床试验，以确定那些风险最大的人。对于申请人来说，这 该计划将加强快速过渡到独立使用短期密集培训， 导师制，这将无缝地与这个拟议的研究方向的目标。

PROJECT SUMMARY The overall goal of this proposed research is to elucidate the mechanisms that may confer increased vulnerability to Alzheimer’s disease (AD)-related cognitive decline in females, using state-of-the-art multi-modal neuroimaging, in both middle and older-aged adults. Females are often reported to exhibit greater rates of clinical progression to AD dementia than males. The applicant’s preliminary data suggest, however, that minimal sex differences exist in amyloid burden, implying other pathophysiologic mechanisms, such as tau, may influence subsequent elevated risk of cognitive decline in older females. It is also critical to investigate the early emergence of sex differences in AD biomarker accumulation during midlife, when sex and hormonal factors may have a particular impact. During the K99 phase, the first aim will identify sex differences in AD neuroimaging biomarkers of amyloid, tau and neurodegeneration in clinically-normal older adults. The second aim will determine relationships between sex and baseline AD biomarkers on longitudinal rates of cognitive decline in the same sample. The primary hypothesis, based on preliminary data, is that women will demonstrate greater tau burden, neurodegeneration and rates of cognitive decline despite similar levels of amyloid burden, likely due to an interaction between sex and APOE genotype. To accomplish these goals, the applicant will leverage existing strengths in statistical modeling and cognitive neuroscience to gain expertise in four critical areas of training: (1) multimodal imaging, (2) data harmonization, (3) longitudinal modeling, and (4) sex biology. With the development of these skills, the applicant will be well positioned in the R00 phase to conduct the final aim: to investigate sex differences in AD biomarker accumulation in middle-aged adults. In addition, the candidate will focus on the influence of hormonal stage (pre-menopause, perimenopause, and menopause) on rates of AD biomarker accumulation relative to age-matched males. A highly innovative component of this project is the use of multimodal neuroimaging (positron emission tomography (PET) and magnetic resonance imaging) and genetics to understand the mechanisms underpinning greater female risk for AD. The proposed study will provide some of the first insights into sex-differences in regional tau-PET burden in preclinical AD in middle and older-age adults. To boost statistical power for detecting sex effects in the K99 phase, data will be harmonized across three well-characterized, longitudinal cohorts of older adults (60-90 years). For the R00 phase, a similar approach will be employed to harmonize data across three longitudinal cohorts of middle-aged adults (40-65 years). Elucidating sex-specific effects on Alzheimer’s disease (AD) risk across the lifespan has far-reaching consequences for understanding the biological mechanisms that catalyze AD risk, and also for better powering clinical trials to identify those are at greatest risk. For the applicant, this program will enhance a rapid transition to independence using a short period of intensive training and mentorship, which will seamlessly intertwine with the aims of this proposed research direction.