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.

项目摘要/摘要阿尔茨海默氏病（AD）是一种毁灭性的，进行性的神经系统疾病，有选择地降解许多老年人的认知 - 当今美国有610万的广告和估计的患病率到2050年，为1,270万。被诊断出患有AD的患者经常患有8 - 10年的疾病，但下降记忆和其他认知能力意味着患者面临独立性丧失和高昂的护理成本（估计在2018年为1860亿美元）。通过有针对性干预措施管理AD风险是必需的一部分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，因为他们在整个生命周期中存在。至关重要的是，遗传AD风险因素可能会偏向大脑和认知发展以增加以后生活的脆弱性。推定的神经发育影响 AD脆弱性基因将与1）早期认知能力的预测能力一致风险和2）AD病理学（例如Aβ沉积）与AD症状相关的广泛变异性（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大多数受广告影响以增加广告漏洞的方式。如果为true，则是受广告影响的大脑的特性结构和大脑网络，例如海马和功能耦合的内存网络将有所不同即使在青年期间也有遗传AD风险。衡量遗传因素如何影响大脑发育将阐明广告风险的终身趋势，同时突出了新的早期干预机会。该项目负责人是一个新的，早期的调查员，具有记忆的认知神经科学背景以及包括神经影像学和神经心理学在内的方法的专业知识。在这项研究中，调查人员将将这些方法应用于对神经发育的早期多基因影响的研究，这可能会影响包括AD在内的晚发神经退行性疾病。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，当前的提案描述了一个新的，紧密的专注的项目旨在填补我们现有知识的关键空白。具体目的是：1）测量与广告相关基因对广告可构成大脑区域的发育差异的影响； 2）量化如何基因影响后来容易受到AD的功能性脑网络的发展； 3）测试发展可归因于广告相关基因的AD可吸收能力的差异。对于这些目标，研究团队将从9、11或13岁的健康青年中开发一个新的数据集（n = 270）结合神经影像学（大脑结构/功能），神经心理学测试（认知）和基因组测定（与广告相关的基因）在纵向设计中。这些数据将改善该领域对紧迫的理解从发展风险的角度来看，广告的临床问题。在研究孩子的同时向广告讲话似乎违反直觉，这种方法可能是解决损失公共卫生的关键一步灾难：当今的一些儿童已准备好成为明天的痴呆症患者。