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

阿尔茨海默病进展中的性别差异：更年期是关键吗？

• 批准号: 10404323
• 负责人: Rachel Frances Buckley
• 金额: $ 24.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404323
• 关键词: Accounting; Address; Adult; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Appearance; Area; Attention; Biological; Biology; Brain; Cerebrospinal Fluid; Clinical; Clinical Trials; Cognitive; Communities; Data; Disease; Education; Elderly; Exhibits; Female; Framingham Heart Study; Frequencies; Future; Gap Junctions; Genetic; Genotype; Glean; Goals; Hippocampus (Brain); Hormonal; Hormonal Change; Impaired cognition; Investigation; Language; Lateral; Life Style; Longevity; Longitudinal cohort; Magnetic Resonance Imaging; Measures; Medial; Memory; Menopause; Mentors; Mentorship; Modeling; Multimodal Imaging; Natural History; Nerve Degeneration; Neurosecretory Systems; Outcome; Pathology; Perimenopause; Phase; Positioning Attribute; Positron-Emission Tomography; Premenopause; Prevention; Process; Registries; Reporting; Research; Risk; Role; Sampling; Sex Differences; Statistical Models; Survivors; Temporal Lobe; Thick; Training; Wisconsin; Woman; aged; aging brain; base; cerebral atrophy; cognitive neuroscience; cognitive testing; cohort; data harmonization; executive function; imaging biomarker; imaging genetics; innovation; insight; male; middle age; mortality risk; multimodality; neuroimaging; neuroimaging marker; pre-clinical; programs; rate of change; sex; skill acquisition; tau Proteins; treatment response; β-amyloid burden

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.

项目摘要 这项拟议研究的总体目标是阐明可能会议增加的机制 使用最先进的多模式 在中年和老年成年人中，神经影像学。据报道，女性表现出更高的率 临床向AD痴呆症的进展比男性。申请人的初步数据表明， 淀粉样蛋白伯嫩中存在最小的性别差异，这意味着其他病理生理机制，例如tau， 可能会影响老年女性认知能力下降的十一风险。调查 性别和马匹期间的广告生物标志物积累的性别差异的早期出现 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 临床正常老年人的淀粉样蛋白，tau和神经退行性的神经影像学生物标志物。第二个 AIM将确定性别和基线AD生物标志物与认知纵向率的关系 同一样本的下降。基于初步数据的主要假设是女性将 证明了更大的tau伯嫩，神经退行性变化和认知下降的速率相似 淀粉样蛋白伯恩，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， 申请人将利用统计建模和认知神经科学中的现有优势来获得专业知识 训练的四个关键领域：（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，申请人将在R00阶段很好地定位于 进行最终目的：研究中年成年人AD生物标志物积累的性别差异。 此外，候选人将专注于激素阶段的影响（春季前，围绕和 更年期）相对于年龄匹配的男性，AD生物标志物积累率。高度创新的 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，以了解女性更大风险的机制 广告。拟议的研究将为区域性tau-pet负担中的性别差异提供一些最早的见解 在中年和老年成年人的临床前广告中。提高检测K99性别影响的统计能力 阶段，数据将在三个特征良好的，纵向同类的老年人中进行协调（60-90 年）。对于R00阶段，将雇用类似的方法来统一三个纵向的数据 中年成年人队列（40 - 65年）。阐明对阿尔茨海默氏病（AD）风险的性别特异性影响 在整个寿命中 AD风险，还可以更好地为临床试验提供更好的供电，以确定这些试验的风险最大。对于申请人，这个 计划将使用短期的密集培训和 Menorship，它将无缝地与该拟议的研究方向的目的无缝地交织在一起。