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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.

项目摘要老年性主要神经认知障碍，包括阿尔茨海默病（AD）和阿尔茨海默病相关性痴呆（ADRD）产生认知能力下降，严重影响日常生活。迄今为止神经退行性变和认知能力下降的分子过程，最终导致 AD/ADRD仍然知之甚少。全基因组关联研究进展为识别AD/ADRD的遗传变异和相关生物学途径提供了有希望的途径风险超出了那些众所周知的APOE基因多态性的特征。然而一个主要 AD/ADRD基因组学进展的挑战是用于诊断AD/ADRD的现代方法，流行病学研究通常依赖于在单一时间点的认知评估或临床评级，被成年早期认知功能峰值水平的实质性变化所混淆。特别当认知功能的峰值水平很高时，认知能力的下降可能会在几十年前被发现，存在功能受损的个体。事实上，现在已经很清楚，到时候进行AD/ADRD诊断，AD/ADRD的病理生理学和加速认知障碍的轨迹，在所谓的“沉默期”，这些问题既冲淡了偏见 GWAS协会在传统的病例对照，时间事件，年龄在事件，和单一场合的设计。因此，当前R 01提案的主要目标是进行第一次基于大型财团的痴呆发作前纵向衰老相关认知变化的连续速率的GWAS。这将使我们能够识别出APOE基因以外的变异，这些变异赋予认知能力下降的风险，对于最终的AD/ADRD，估计改善的全基因组多基因评分可用于增强评估AD/ADRD风险，并确定AD/ADRD风险的新生物学途径，预防和治疗工作。