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

项目概要 衰老引起的主要神经认知障碍，包括阿尔茨海默病 (AD) 和阿尔茨海默病 相关痴呆症 (ADRD) 会导致认知能力下降，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（GWAS）的最新进展 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 风险超出了众所周知的 APOE 基因内的多态性特征。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 流行病学研究通常依赖于单个时间点的认知评估或临床评级，这 成年早期认知功能峰值水平的巨大差异使人们感到困惑。特别是 当认知功能的峰值水平很高时，认知能力下降可能会在几十年前未被发现 功能水平受损的个体。事实上，现在已经很清楚了，到时候 AD/ADRD 诊断、AD/ADRD 的病理生理学和加速认知轨迹 在所谓的“沉默期”，衰退已经广泛积累。这些问题既淡化又偏见 传统病例对照、事件发生时间、事件年龄和单一事件设计中的 GWAS 关联。 因此，当前 R01 提案的主要目标是进行第一个基于联盟的大规模 痴呆症发病前纵向衰老相关认知变化连续率的 GWAS。这将 使我们能够识别 APOE 基因中的变异体，这些变异体会带来导致认知能力下降的风险 为了最终的 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，并确定可针对 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.