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

项目总结 这项拟议的研究的总体目标是阐明可能导致 使用最先进的多模式测试，女性易受阿尔茨海默病(AD)相关认知能力下降的影响 无论是中老年人还是老年人的神经成像。据报道，女性通常表现出更高的 临床进展为阿尔茨海默病的患者多于男性。然而，申请人的初步数据表明， 淀粉样蛋白负荷存在极小的性别差异，这意味着其他病理生理机制，如tau， 可能会影响随后老年女性认知能力下降的风险增加。同样重要的是调查 AD生物标记物积累的性别差异在中年、性行为和荷尔蒙的早期出现 这些因素可能会产生特别的影响。在K99阶段，第一个目标是确定AD的性别差异 临床正常老年人中淀粉样蛋白、tau蛋白和神经变性的神经成像生物标记物。第二 AIM将确定性别和基线AD生物标记物之间的关系，以影响认知能力的纵向比率 在同一样本中呈下降趋势。基于初步数据的主要假设是，女性会 表现出更大的tau负担，神经变性和认知减退率，尽管水平相似 淀粉样蛋白负荷，可能是由于性别和载脂蛋白E基因之间的相互作用。为了实现这些目标， 申请者将利用统计建模和认知神经科学方面的现有优势获得以下方面的专业知识 培训的四个关键领域：(1)多模式成像、(2)数据协调、(3)纵向建模和(4) 性生物学。随着这些技能的发展，申请者将在R00阶段处于有利地位 最终目的：探讨中年人AD生物标记物积累的性别差异。在……里面 此外，候选人将重点关注荷尔蒙阶段(绝经前、围绝经期和 绝经)与年龄匹配的男性相比，AD生物标记物积累率。一款极具创新性的 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，以了解女性患癌症风险更高的机制 广告。这项拟议的研究将为研究地区tau-PET负荷的性别差异提供一些初步的见解 在中老年人的临床前AD中。在K99中提高检测性影响的统计能力 在这一阶段，数据将在三个特征良好的纵向老年人(60-90岁)队列中进行协调 年)。对于R00阶段，将使用类似的方法来协调三个纵向的数据 中年人(40-65岁)队列。阐明性别对阿尔茨海默病(AD)风险的影响 对于理解催化的生物机制有着深远的影响 AD风险，以及更好地推动临床试验，以确定哪些风险最大。对于申请人来说，这是 该计划将通过短期的强化培训和培训来促进快速过渡到独立 导师制，这将与这一拟议研究方向的目标无缝地交织在一起。

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.