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

男性和女性患阿尔茨海默氏症的情况不同，但我们不知道原因。当身体健康时，女性往往会表现出 在口头记忆任务上表现更好，但一旦AD站稳脚跟，在这些任务上就会比男性衰退得更快。确实有 其他认知领域的性别差异也是如此。尽管有这些已知的认知能力和运动轨迹的差异 我们衡量AD变化的工具没有充分考虑到性别差异。此外，风险因素 包括遗传风险和血管风险的风险因性别而异。同样，这在很大程度上被研究忽视了，但可能代表着重要的 这些差异可能会在精确医学中发挥作用。此外，我们从尸检和生物标记物研究中得知 女性大脑中tau的数量和分布超过男性，而且与男性不同。拟议的项目将 对PAR-19-070的反应：阿尔茨海默病及其相关痴呆的当前主题研究 与NOT-AG-18-053合作：阿尔茨海默病和相关痴呆流行病学研究的重大机遇 和认知韧性。我们将探讨这些认知表达、遗传和血管风险方面的已知差异， 和病理生理学，以更好地了解AD在疾病的早期阶段对女性和男性的影响。我们希望 揭示相似和不同之处，这可能在新疗法和新疗法的开发中至关重要 测试它们的方法。在目标1和目标2中，我们将使用两个现有的数据集来创建新的特定于性别的工具 从纵向数据派生而来的组合。这些经验派生的、加权最优的复合材料可用于 评估临床试验和观察性研究中随时间的变化。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比那些可能更性别偏见的测试更具性别可知性。我们 将了解遗传风险，应用新开发的性别特定多基因风险评分来评估这些 有助于预测所有数据集的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的性别差异，特别是如何 认知与男性和女性体内tau的数量和分布有关。我们将使用的数据集都使用tau PET， 这使我们能够调查与认知有关的地区分布。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有关。通过采取 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 并对这种疾病有了更深入的了解。该项目将对公共卫生产生直接影响，确定如何 针对不同性别的研究可以丰富我们对本病的症状、病程、危险因素和病理生理学的了解。 广告。这可以被翻译成用于临床试验、流行病学和观察性研究，甚至可能用于 开发新的性靶向治疗方法。

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.