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

项目总结 老年性主要神经认知障碍，包括阿尔茨海默病和阿尔茨海默病 相关痴呆症(ADRD)会导致认知能力下降，严重影响日常生活。到目前为止， 神经退行性变和认知衰退的分子过程最终导致 人们对AD/ADRD仍知之甚少。全基因组关联研究的最新进展 为识别AD/ADRD的遗传变异和相关的生物学途径提供了有希望的途径 风险超过那些以众所周知的载脂蛋白E基因的多态为特征的。然而，一个主要的 AD/ADRD基因组学进展面临的挑战是，用于诊断AD/ADRD的当代方法 流行病学研究往往依赖于单一时间点的认知评估或临床评级，这 在成年早期认知功能的峰值水平有很大的差异，这让他们感到困惑。尤其是 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不被察觉 存在功能受损水平的个人。事实上，现在已经很明显，到了那个时候 AD/ADRD的诊断、AD/ADRD的病理生理学和加速认知轨迹 在所谓的“静默期”，下降已经广泛累积。这些问题都是冲淡和偏见的。 传统病例对照、事件发生时间、事件发生年龄和单一事件设计中的GWAS相关性。 因此，目前R01提案的主要目标是进行第一个以大型财团为基础的 在痴呆症发作之前，与衰老相关的认知变化的持续比率。这将是 允许我们识别APOE基因以外的变异，这些变异会导致认知功能减退的风险 对于最终的AD/ADRD，估计改善的全基因组多基因得分，可用于增强 评估AD/ADRD风险，并确定可以针对的AD/ADRD风险的新生物途径 预防和治疗工作。

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.