Shared Genetic and Environmental Influences on Age-Related Hearing Loss, Cognitive Decline, and Dementia Risk

项目摘要/摘要 良好的听力和认知能力是保持晚年生活质量的关键，但随着年龄的增长，听力和认知能力会下降。 听力阈值和认知能力是相关的，年龄相关感音神经性听力的诊断 丢失会增加阿尔茨海默病和相关痴呆症的风险。这些发现表明，共有的基因 环境因素影响老年性耳聋、认知能力下降和痴呆症的风险。我们称其为“COM- MON途径“假说。在我们之前对随机选择的墨西哥裔美国人儿童的研究中- GREES，我们发现听力和认知能力之间的遗传关联，为常见的 路径假说。然而，具体的共同遗传和环境途径尚未确定。 被吓到了。在这里，我们建议测量听力、认知能力和推测的痴呆症生物标记物(t- Tau、p-tau、Aβ42/40和NF-L)在另外600名墨西哥裔美国人中)，增加了我们的总样本 规模达到1,300人，从而为进一步分析提供足够的动力，包括识别特定的Ge-1。 磁性/环境风险因素。我们的具体目标是(1)量化与年龄相关的和共同的遗传影响 关于听力、认知和痴呆症的生物标志物；(2)询问全基因组序列数据，医学上的 形成和地理空间数据，以确定对这些性状的具体遗传和环境影响； (3)提供听力损失和痴呆症风险本身之间的多效性的直接证据；及(4)验证 耳蜗性突触的测量，这是一种听力损失的生理预警信号，无法通过 传统的听力测试，作为未来衰老研究的表型。测量听力，认知能力， 在相同的个体中，痴呆症生物标志物的共同作用可能会极大地提高描绘出 影响衰老的这些关键方面中的一个或多个的特定因素。这样的发现反过来可能会提供 增加成功老龄化的美国人数量的见解和策略。塞缪尔·马蒂亚斯博士 波士顿儿童医院的大卫·格拉恩和德克萨斯大学格兰德·瓦尔大学的约翰·布兰杰罗博士 莱伊是这项申请的联合首席调查员。德克萨斯大学健康科学分校的艾米·加勒特博士 圣安东尼奥中锋将领衔一份转包合同。鉴于丰富的表型、环境和遗传数据 已在该队列中提供，建议的研究代表了一种易于获得、成本效益高和功能强大的 阐明衰老机制的资源。

PROJECT SUMMARY/ABSTRACT Good hearing and cognitive skills are critical to maintaining later-life quality yet decline with advancing age. Hearing thresholds and cognitive abilities are correlated, and a diagnosis of age-related sensorineural hearing loss increases risk for Alzheimer’s disease and related dementias. These findings suggest that shared genetic and environmental factors influence presbycusis, cognitive decline, and dementia risk. We call this the “com- mon pathway” hypothesis. In our previous study of individuals from randomly selected Mexican American pedi- grees, we found genetic correlations between hearing and cognitive abilities, providing support for the common pathway hypothesis. However, the specific common genetic and environmental pathways have yet to be identi- fied. Here, we propose to measure hearing abilities, cognitive abilities, and putative dementia biomarkers (t- tau, p-tau, Aβ42/40, and NF-L) in an additional 600 Mexican American participants, increasing our total sample size to 1,300 and thereby providing sufficient power for further analyses, including identification of specific ge- netic/environmental risk factors. Our specific aims are (1) to quantify age-related and shared genetic influences on hearing, cognition, and dementia biomarkers; (2) to interrogate whole-genome sequence data, medical in- formation, and geospatial data in order to identify specific genetic and environmental influences on these traits; (3) to provide direct evidence of pleiotropy between hearing loss and dementia risk per se; and (4) to validate measures of cochlear synaptopathy, a physiological early warning sign of hearing loss that is undetectable via traditional hearing tests, as phenotypes for future aging studies. Measuring hearing abilities, cognitive abilities, and dementia biomarkers together in the same individuals may dramatically improve the odds of delineating specific factors influencing one or more of these crucial aspects of aging. Such discoveries may in turn provide insights and strategies for increasing the numbers of Americans who successfully age. Drs. Samuel Mathias and David Glahn at Boston Children’s Hospital and Dr. John Blangero at University of Texas Rio Grande Val- ley are co-principal investigators on this application. Dr. Amy Garrett at University of Texas Health Science Center San Antonio will lead a subcontract. Given the wealth of phenotypic, environmental and genetic data already available in this cohort, the proposed study represents a readily available, cost-effective, and powerful resource for elucidating the mechanisms of aging.