权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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/摘要阿尔茨海默病(AD)是一种毁灭性的进行性神经疾病，它选择性地降解许多老年人的认知--目前美国有610万AD患者，估计患病率到2050年是1270万。被诊断为阿尔茨海默病的患者通常会因此而存活8-10年，但在记忆力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费用 (2018年估计为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和影响AD风险的遗传因素将对这些努力至关重要，因为它们在整个生命周期中都存在。关键是，遗传性阿尔茨海默病的风险因素可能会使大脑产生偏见，并认知发展使人在晚年更容易患上老年痴呆症。一种可能的神经发育影响 AD易感性的基因与1)早期认知能力对晚期AD的预测力是一致的风险，以及2)AD病理(例如，β沉积)与AD症状(例如，失忆)。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受AD影响最大的是增加AD脆弱性的方式。如果是真的，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的记忆网络将有所不同即使在青年时期也有遗传性阿尔茨海默病风险。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。项目负责人是一位新的、处于早期阶段的研究人员，具有记忆认知神经科学方面的背景以及神经成像和神经心理学等方法方面的专业知识。在这项研究中，调查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，这些效应可能会影响高血压的风险包括阿尔茨海默病在内的迟发性神经退行性疾病。来自大型发展数据集的关键初步数据为这一假说提供了重要的早期支持，而当前的提议描述了一种新的、紧密的有重点的项目，旨在填补我们现有知识的关键空白。具体目标是：1)衡量 AD相关基因对阿尔茨海默病易感脑区发育差异的影响；2)量化基因影响后来易患阿尔茨海默病的功能性脑网络的发育；3)测试发育阿尔茨海默病易感认知能力的差异与AD相关基因有关。为了达到这些目标，这项研究研究小组将从9岁、11岁或13岁的健康青年的大样本(N=270)中开发一个新的数据集结合神经成像(大脑结构/功能)、神经心理测试(认知)和基因组分析 (广告相关基因)在纵向设计中。这些数据将提高现场对紧迫问题的理解从发育风险角度看阿尔茨海默病的临床问题同时通过研究儿童来应对AD 这种方法似乎有违常理，可能是解决迫在眉睫的公共卫生问题的关键一步灾难：今天的一些孩子已经准备好成为明天的痴呆症患者。