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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

基本信息

批准号：
10823789
负责人：
David E Warren
金额：
$ 4.28万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目概要/摘要阿尔茨海默氏病 (AD) 是一种破坏性、进行性神经系统疾病，可选择性地降低大脑功能许多老年人的认知——当今美国有 610 万人患有 AD，估计患病率到 2050 年将达到 1270 万。诊断为 AD 的患者通常可以存活 8-10 年，但寿命会下降记忆和其他认知能力意味着患者面临失去独立性和高昂的护理费用（2018 年预计为 1860 亿美元）。通过有针对性的干预措施管理 AD 风险是必要的一部分我们的公共卫生应对措施以及影响 AD 风险的遗传因素对于这些努力至关重要，因为它们存在于整个生命周期。至关重要的是，遗传性 AD 风险因素可能会对大脑和大脑产生偏见。认知发展会增加日后患 AD 的可能性。假定的神经发育影响 AD 易感性基因与 1) 早期认知能力对后期 AD 的预测能力一致风险，2) AD 病理学（例如 Aβ 沉积）与 AD 症状学（例如，记忆丧失）。在这里，我们假设基因组 AD 风险会改变大脑系统的神经发育受 AD 影响最大的方式是增加 AD 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（例如海马体和功能耦合记忆网络）会有所不同即使在青少年时期也有遗传性 AD 风险。测量遗传因素如何影响大脑发育将阐明 AD 风险的终生趋势，同时强调早期干预的新机会。该项目负责人是一位新的早期研究人员，具有记忆认知神经科学背景以及神经影像学和神经心理学等方法的专业知识。在这项研究中，研究人员将将这些方法应用于研究可能影响神经发育风险的早期多基因效应迟发性神经退行性疾病，包括 AD。来自大型发育数据集的关键初步数据为这一假设提供了重要的早期支持，当前的提案描述了一种新的、紧密的旨在填补我们现有知识的关键空白的重点项目。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）量化如何基因影响大脑功能网络的发育，而这些网络随后很容易患阿尔茨海默病； 3) 测试发育 AD 相关基因导致 AD 易受影响的认知能力存在差异。为了这些目标，研究团队将从 9 岁、11 岁或 13 岁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影像学（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）纵向设计。这些数据将提高该领域对紧迫问题的理解从发育风险角度看 AD 的临床问题。通过研究儿童来解决AD问题看似违反直觉，但这种方法可能是解决迫在眉睫的公共卫生问题的关键一步灾难：今天的一些儿童可能会成为明天的痴呆症患者。