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

遗传和环境对与年龄相关的听力损失、认知能力下降和痴呆风险的共同影响

• 批准号: 10658077
• 负责人: John Blangero
• 金额: $ 77.16万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658077
• 关键词: 18 year old; Age; Aging; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Amyloid beta-42; Animals; Audiology; Auditory Threshold; Biological; Biological Markers; Blood; Blood specimen; Boston; Brain; Case/Control Studies; Cognition; Cognitive; Data; Dementia; Diagnosis; Elderly; Environmental Risk Factor; Ethnic Origin; Family history of; Follow-Up Studies; Future; Genes; Genetic; Genetic Variation; Genetic study; Genomic Segment; Genomics; Genotype; Health; Health Sciences; Hearing; Hearing Tests; Heritability; Human; Image; Impaired cognition; Individual; Lead; Life; Link; Measures; Medical; Mental Health; Mexican Americans; Neurofilament-L; Participant; Pathogenesis; Pathway interactions; Pediatric Hospitals; Pharmaceutical Preparations; Phenotype; Physiological; Population; Presbycusis; Prevalence; Principal Investigator; Quality of life; Random Allocation; Research; Research Personnel; Resources; Role; Sample Size; Sampling; Sensorineural Hearing Loss; Structure; Testing; Texas; Universities; Variant; age related; aging brain; aging population; cochlear synaptopathy; cognitive ability; cognitive skill; cohort; comorbidity; cost effective; dementia risk; design; endophenotype; genetic pedigree; genome wide association study; hearing impairment; improved; indexing; insight; normal hearing; novel; pathological aging; physical conditioning; pleiotropism; tau Proteins; tau-1; trait; whole genome

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.

项目总结/摘要 良好的听力和认知能力对维持晚年生活质量至关重要，但会随着年龄的增长而下降。 听力阈值和认知能力是相关的，诊断与年龄相关的感音神经性听力 损失增加患阿尔茨海默病和相关痴呆症的风险。这些发现表明， 环境因素影响老年性耳聋、认知能力下降和痴呆风险。我们称之为“com- mon pathway假说。在我们以前的研究中，随机选择的墨西哥裔美国人的pedi- 我们发现了听力和认知能力之间的遗传相关性，为听力和认知能力之间的共同关系提供了支持。 路径假说然而，具体的共同遗传和环境途径尚未确定。 fied。在这里，我们建议测量听力能力，认知能力和推定的痴呆生物标志物（t- tau、p-tau、Aβ42/40和NF-L），增加了我们的总样本量 大小为1，300，从而为进一步分析提供足够的功率，包括识别特定的锗- 遗传/环境风险因素。我们的具体目标是（1）量化年龄相关的和共享的遗传影响 听力，认知和痴呆生物标志物;（2）询问全基因组序列数据，医学信息， 形成和地理空间数据，以确定对这些特征的特定遗传和环境影响; (3)提供听力损失和痴呆风险本身之间多效性的直接证据;（4）验证 耳蜗突触病的测量，这是听力损失的生理早期预警信号，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， 和痴呆生物标志物在同一个人身上一起使用， 影响衰老的一个或多个关键方面的特定因素。这些发现可能反过来提供 增加成功老龄化的美国人数量的见解和策略。Samuel Mathias博士 还有波士顿儿童医院的大卫格拉恩和德克萨斯大学格兰德河瓦尔的约翰布朗杰罗博士 李是该申请的共同主要研究者。德克萨斯大学健康科学系的艾米加勒特博士 中锋圣安东尼奥将领先一分。鉴于丰富的表型、环境和遗传数据 已经在这个队列中可用，拟议的研究代表了一个现成的，具有成本效益的，强大的 阐明衰老机制的资源。