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

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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.