Large-Scale Genomic Analysis of Aging-Related Cognitive Change Prior to Dementia Onset

痴呆症发病前与衰老相关的认知变化的大规模基因组分析

基本信息

批准号：
10280400
负责人：
Elliot Max Tucker-Drob
金额：
$ 206.07万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10280400
关键词：
Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease diagnosis Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Basic Science Biological Birth Brain imaging Categories Clinical Data Data Analyses Dementia Development Diagnosis Diffusion Magnetic Resonance Imaging Elderly Equation Ethics Event Exercise Functional disorder Genes Genetic Genetic Polymorphism Genetic Risk Genomics Genotype Goals Health and Retirement Study Health behavior Impaired cognition Impairment Individual Intervention Longitudinal Studies Measures Memory Methods Modeling Molecular Nerve Degeneration Neurobiology Neurons Participant Persons Phenotype Prevention Process Risk Sampling Smoking Societies Structure Time Validation Variant base biological sex cardiovascular health case control clinical application cognitive change cognitive function cognitive testing cohort dementia risk design emerging adult epidemiology study genetic association genetic risk factor genetic variant genome wide association study genome-wide improved indexing innovation neurocognitive disorder neurophysiology novel physical conditioning prevent processing speed psychosocial relating to nervous system risk sharing structural genomics

项目摘要

PROJECT SUMMARY Major Neurocognitive Disorders of Aging, including Alzheimer's Disease (AD) and Alzheimer's Disease Related Dementias (ADRD), produce cognitive declines that substantially affect daily living. To date, the molecular processes underlying the neurodegeneration and cognitive declines that ultimately give rise to AD/ADRD remain poorly understood. Recent developments in genome wide association study (GWAS) provide promising avenues for identifying genetic variants and associated biological pathways of AD/ADRD risk beyond those characterized by polymorphisms within the well-known APOE gene. However, a major challenge to progress in AD/ADRD genomics is that contemporary methods used to diagnose AD/ADRDs for epidemiological research often rely on cognitive assessments or clinical rating at a single point in time, which are confounded by substantial variation in peak levels of cognitive function in early adulthood. Particularly when peak levels of cognitive function are high, cognitive declines may go undetected for decades before individuals present with impaired levels of functioning. Indeed, it has now become clear that by the time AD/ADRD diagnoses are made, the pathophysiology of AD/ADRD and trajectories of accelerated cognitive decline have accumulated extensively, during a so-called “silent period.” These issues both dilute and bias GWAS associations in conventional case-control, time-to-event, age-at-event, and single occasion designs. The primary goal of the current R01 proposal is therefore to conduct the first large-scale consortium-based GWAS of continuous rates of longitudinal aging-related cognitive change prior to dementia onset. This will allow us to identify variants beyond those in the APOE gene that confer risk for rate of cognitive decline leading to eventual AD/ADRD, estimate improved genome-wide polygenic scores that can be used to enhance assessment of AD/ADRD risk, and identify novel biological pathways of AD/ADRD risk that can be targeted by prevention and treatment efforts.

项目摘要衰老的主要神经认知疾病，包括阿尔茨海默氏病（AD）和阿尔茨海默氏病相关的痴呆症（ADRD）产生的认知下降，迄今为止会影响日常生活神经变性和认知能力下降的分子过程最终引起。 AD/ADRD在基因组广泛协会研究（GWAS）的最新发展中仍然很糟糕。提供有希望的途径来识别AD/ADRD的遗传变异和相关的生物学途径但是，众所周知的APOE基因中的多态性的风险广告/ADRD基因组学进展的挑战是用于诊断AD/ADRD的当代方法流行病学研究通常依赖于单个时间点的认知评估或临床评级，成年初期认知功能的峰值水平的实质性变化使人感到困惑。当认知功能的峰值水平很高时，认知下降可能会在数十年之前未被发现个人的功能确实存在。进行了AD/ADRD诊断，是加速认知的AD/AD轨迹的病理生理学在所谓的“沉默时期”中，下降累积了。 GWAS在常规案例控制，事件的时间，年龄和单场设计中的协会。当前R01提案的主要目标是与基于火灾的联盟联系在发作之前，与纵向老化相关的认知的连续率允许我们识别超出APOE基因中的变体，该变异基因的锥形结束了认知能力下降的领先为了最终的AD/ADRD，估计改进的全基因组多基因分数可用于增强评估AD/ADRD风险，并确定AD/ADRD风险的新型新型生物学途径，可以由预防和治疗。