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.

项目概要 这项研究的总体目标是阐明可能增加 使用最先进的多模式方法，评估女性易受阿尔茨海默病 (AD) 相关认知能力下降的影响 据报道，中年和老年女性的神经影像学表现出更高的发生率。 然而，申请人的初步数据表明，AD 痴呆的临床进展率高于男性。 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，例如 tau、 可能会影响老年女性随后认知能力下降的风险升高，调查这一点也很重要。 中年期间，当性别和荷尔蒙变化时，AD 生物标志物积累中的性别差异很早就出现 在 K99 阶段，第一个目标是确定 AD 中的性别差异。 临床正常老年人中淀粉样蛋白、tau 蛋白和神经变性的神经影像生物标志物。 目标将确定性别和基线 AD 生物标志物在认知纵向率上的关系 根据初步数据，同一样本中的主要假设是女性会下降。 尽管 tau 蛋白水平相似，但表现出更大的 tau 负担、神经变性和认知能力下降率 淀粉样蛋白负担，可能是由于性别和 APOE 基因型之间的相互作用造成的。 申请人将利用统计建模和认知神经科学的现有优势来获得以下方面的专业知识 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) 随着这些技能的发展，申请人将在 R00 阶段处于有利地位 进行的最终目标是：调查中年成人 AD 生物标志物积累的性别差异。 此外，考生将重点关注荷尔蒙阶段（绝经前、围绝经期和绝经期）的影响。 更年期）对年龄匹配男性 AD 生物标志物相对积累率的影响。 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，以了解女性患病风险更大的机制 AD。拟议的研究将为区域 tau-PET 负担的性别差异提供一些初步见解。 在中老年人的临床前 AD 中提高检测 K99 性别影响的统计能力。 阶段，数据将在三个特征明确的老年人纵向队列（60-90 对于 R00 阶段，将采用类似的方法来协调三个纵向数据。 阐明性别对阿尔茨海默病 (AD) 风险的影响。 整个生命周期对于理解催化的生物机制具有深远的影响 AD 风险，以及更好地支持临床试验来识别那些对申请人来说风险最大的人。 计划将通过短期强化培训和促进快速过渡到独立 指导，这将与该拟议研究方向的目标无缝地交织在一起。