Measuring neurodevelopmental effects of polygenic risk for Alzheimer's disease via longitudinal study of brain and cognitive variables in periadolescent children

通过对青春期儿童大脑和认知变量的纵向研究来测量阿尔茨海默病多基因风险对神经发育的影响

• 批准号: 10613526
• 负责人: David E Warren
• 金额: $ 58.79万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613526
• 关键词: Address; Adolescent; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Anterior; Biological Assay; Brain; Brain region; Child; Childhood; Clinical; Cognition; Cognitive; Complex; Coupled; Data; Data Set; Dementia; Development; Diagnosis; Disease; Early Intervention; Elderly; Enrollment; Environment; Face; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Risk; Genomics; Goals; Hippocampus; Intervention; Knowledge; Late Onset Alzheimer Disease; Lead; Life; Longevity; Longitudinal Studies; Manuals; Measures; Memory; Memory Loss; Methods; Nerve Degeneration; Neurodegenerative Disorders; Neuropsychological Tests; Neuropsychology; Patients; Persons; Population; Prevalence; Property; Public Health; Research; Research Personnel; Research Project Grants; Rest; Risk; Risk Factors; Risk Reduction; Sampling; Structure; System; Techniques; Testing; Thick; Thinness; United States National Institutes of Health; Youth; abeta deposition; aged; care costs; cognitive ability; cognitive development; cognitive enhancement; cognitive neuroscience; cognitive testing; design; executive function; genome-wide; hippocampal atrophy; improved; indexing; individual variation; innovation; insight; longitudinal design; negative affect; nervous system disorder; neurodevelopment; neurodevelopmental effect; neuroimaging; novel; periadolescent; response; risk variant; sex; trend; whole genome

Project Summary/Abstract Alzheimer’s disease (AD) is a devastating, progressive neurological disorder that selectively degrades the cognition of many older adults — 6.1 million are living with AD in the US today and the estimated prevalence by 2050 is 12.7 million. Patients diagnosed with AD often live 8-10 years with the disease, but declines in memory and other cognitive abilities mean that patients face loss of independence and high costs of care (estimated to be $186 billion in 2018). Management of AD risk with targeted interventions is a needed part of our public health response, and genetic factors affecting AD risk will be essential to those efforts because they are present throughout the lifespan. Critically, it is possible that genetic AD risk factors may bias brain and cognitive development to increase vulnerability to AD later in life. A putative neurodevelopmental influence of genes on AD vulnerability would be consistent with 1) the predictive power of early cognitive ability for later AD risk, and 2) wide variability in how AD pathology (e.g., Aβ deposition) relates to AD symptomology (e.g., memory loss). Here, we hypothesize that genomic AD risk alters neurodevelopment of the brain systems most affected by AD in ways that increase AD vulnerability. If true, then properties of AD-affected brain structures and brain networks such as the hippocampus and functionally-coupled memory networks will vary with genetic AD risk even during youth. Measuring how genetic factors affect brain development will elucidate lifelong trends for AD risk while highlighting new opportunities for early intervention. The project lead is a new, early-stage investigator with a background in the cognitive neuroscience of memory and expertise in methods including neuroimaging and neuropsychology. In this study the investigators will apply these methods to the study of early polygenic effects on neurodevelopment that may affect the risk of late-onset neurodegenerative diseases including AD. Key preliminary data from large developmental datasets have provided important early support for this hypothesis, and the current proposal describes a new, tightly focused project designed to fill critical gaps in our existing knowledge. The Specific Aims are: 1) Measure effects of AD-related genes on developmental differences in AD-vulnerable brain regions; 2) Quantify how genes affect development of functional brain networks that are later vulnerable to AD; 3) Test developmental differences in AD-vulnerable cognitive abilities attributable to AD-related genes. For these Aims, the research team will develop a new dataset from a large sample (N=270) of healthy youths aged 9, 11, or 13 years by combining neuroimaging (brain structure/function), neuropsychological tests (cognition), and genomic assays (AD-related genes) in a longitudinal design. These data will improve the field’s understanding of the pressing clinical problem of AD from a developmental risk perspective. While addressing AD by studying children appears counterintuitive, this approach may be a crucial step toward addressing a looming public health catastrophe: some of today’s children are primed to become tomorrow’s dementia patients.

项目总结/摘要 阿尔茨海默氏病（AD）是一种破坏性的、进行性的神经系统疾病，其选择性地降低脑组织中的 许多老年人的认知-今天在美国有610万人患有AD， 到2050年是1270万。被诊断患有AD的患者通常与疾病一起生活8 - 10年，但随着年龄的增长而下降。 记忆和其他认知能力意味着患者面临独立性的丧失和高昂的护理费用 （2018年预计为1860亿美元）。通过有针对性的干预措施管理AD风险是 我们的公共卫生反应，以及影响AD风险的遗传因素对这些努力至关重要，因为它们 存在于整个生命周期中。重要的是，遗传性AD风险因素可能会偏向大脑， 认知发展增加了晚年对AD的易感性。一种假定的神经发育影响， 基因对AD易感性的影响与1）早期认知能力对晚期AD的预测能力一致 风险，和2）AD病理学如何变化的广泛差异（例如，A β沉积）涉及AD病理学（例如， 记忆丧失）。在这里，我们假设基因组AD风险改变了大脑系统的神经发育 最受AD影响的方式是增加AD的脆弱性。如果属实，那么受AD影响的大脑的特性 结构和大脑网络，如海马体和功能耦合记忆网络， 即使在年轻时也有遗传性AD风险。测量遗传因素如何影响大脑发育将阐明 AD风险的终身趋势，同时强调早期干预的新机会。 该项目的负责人是一个新的，早期的研究人员在记忆的认知神经科学的背景 以及神经影像学和神经心理学方面的专业知识。在这项研究中，研究人员将 将这些方法应用于研究早期多基因对神经发育的影响，这些影响可能影响神经发育的风险。 迟发性神经退行性疾病，包括AD。来自大型发展数据集的关键初步数据 已经为这一假设提供了重要的早期支持，目前的建议描述了一个新的，紧密的 重点项目旨在填补我们现有知识的关键空白。具体目标是：（1）测量 AD相关基因对AD易感脑区发育差异的影响; 2）量化如何 基因影响功能性大脑网络的发育，这些网络后来易受AD的影响; 3）测试发育 归因于AD相关基因的AD易感认知能力的差异。为了实现这些目标，研究 研究小组将从9岁、11岁或13岁的健康青少年的大样本（N = 270）中开发一个新的数据集， 结合神经成像（大脑结构/功能）、神经心理学测试（认知）和基因组分析 （AD相关基因）的纵向设计。这些数据将提高该领域对紧迫问题的理解 从发展风险的角度来看AD的临床问题。通过研究儿童来解决AD的同时， 这种方法似乎违反直觉，但它可能是解决迫在眉睫的公共卫生问题的关键一步。 灾难：今天的一些儿童很可能成为明天的痴呆症患者。