Sex-specific cognitive expression and risk in preclinical Alzheimer's disease

男性和女性对阿尔茨海默氏症的体验不同，但我们不知道为什么。当健康的时候，女性往往表现出 在非文字记忆任务上，男性表现得更好，但一旦AD形成，在这些任务上的表现会比男性下降得更快。有 在其他认知领域也存在性别差异。尽管这些已知的认知能力和轨迹的差异， 尽管AD的发病率下降，但我们测量AD变化的工具没有充分考虑性别差异。此外，风险因素 包括遗传和血管风险因性别而异。同样，这在很大程度上被忽视的研究，但可能代表重要的 这些差异可能在精准医疗中发挥作用。此外，我们从尸检和生物标记研究中得知， 女性大脑中tau蛋白的数量和分布超过并不同于男性。拟议项目将 PAR-19 - 070：阿尔茨海默病及其相关痴呆症当前主题的研究，结合 与NOT-AG-18 - 053：阿尔茨海默病和相关痴呆症流行病学研究的主要机会 和认知恢复力我们将在认知表达、遗传和血管风险方面探讨这些已知的差异， 和病理生理学，以更好地了解在疾病的最早阶段的妇女和男子的AD。我们期望 揭示了相似性和差异性，这可能对开发新的治疗方法至关重要， 方法来测试它们。在目标1和2中，我们将利用两个现有的数据集来创建新的工具， 从纵向数据来看，这些经验得出的最佳加权复合材料可用于 在临床试验和观察性研究中评估随时间的变化。由于队列使用不同的认知测试， 电池，我们将了解哪些测试可能更性别不可知论相比，那些可能更性别偏见。我们 将了解遗传风险，应用新开发的性别特异性多基因风险评分来评估这些风险 有助于预测数据集中男性和女性的认知变化，我们将接近血管风险 同样，男性和女性的得分也不同。在目标3中，我们将评估tau蛋白的性别差异，特别是如何 认知与男性和女性中的tau数量和分布有关。我们将使用的数据集都采用tau PET， 让我们能够研究认知的区域分布。我们希望找到重要的和交织在一起的 认知表达和风险的差异，以及这些与潜在的病理生理学相关。以 利用现有的队列数据，我们希望为未来的研究铺平道路，将我们的研究扩展到更多样化的领域。 队列和对疾病的更深入了解。该项目将对公共卫生产生直接影响，确定如何 性别特异性方法可以丰富我们对乳腺癌的发病学、病程、危险因素和病理生理学的理解， AD.这可以用于临床试验、流行病学和观察性研究，甚至可能用于 开发新的针对性治疗方法。

Men and women experience Alzheimer's differently, but we do not know why. When healthy, women tend to perform better on verbal memory tasks, but then decline more quickly than men on these tasks once AD takes hold. There are sex differences in other cognitive domains too. Despite these know differences in cognitive ability and trajectories of decline, our tools to measure change in AD do not adequately take sex differences into account. In addition, risk factors including genetic and vascular risk differ by sex. Again this is largely ignored in research, yet may represent important differences which could have a role in precision medicine. Furthermore, we know from autopsy and biomarker studies that the amount and distribution of tau in the brains of women exceeds and differs from men. The proposed project will respond to PAR‐19‐070: Research on Current Topics in Alzheimer's Disease and Its Related Dementias, in combination with NOT‐AG‐18‐053: Major Opportunities for Research in Epidemiology of Alzheimer's Disease and Related Dementias and Cognitive Resilience. We will approach these known differences in cognitive expression, genetic and vascular risk, and pathophysiology to better understand AD in women and men at the earliest stages of the disease. We expect to reveal similarities and differences, which might be of central importance in the development of novel therapeutics and approaches to test them. In Aims 1 and 2 we will employ two existing datasets to create new tools, sex‐specific composites, derived from longitudinal data. These empirically derived, optimally weighted composites can be used to assess change over time in clinical trials and observational studies. Since the cohorts use different cognitive test batteries, we will learn which tests might be more sex‐agnostic compared to those which might be more sex‐biased. We will learn about genetic risk, applying newly developed sex‐specific polygenic hazard scores to assess how well these contribute to predict cognitive change in men and women across the datasets, and we will approach vascular risk similarly, with distinct scores for men and women. In Aim 3, we will assess sex differences in tau and specifically how cognition relates to tau quantity and distribution in men and women. The datasets we will use both employ tau PET, allowing us to investigate regional distribution in relation to cognition. We expect to find important and intertwined differences in cognitive expression, and risk, and for these to be related to underlying pathophysiology. By taking advantage of existing cohort data we hope to pave the way for future studies extending our research into more diverse cohorts and a deeper understanding of the disease. This project will have direct public health impact, identifying how a sex‐specific approach can enrich our understanding of the symptomatology, course, risk factors and pathophysiology in AD. This can be translated for use in clinical trials, epidemiologic and observational studies, and even potentially the development of new sex‐targeted treatments.