PROJECT ABSTRACT The FMR1 premutation (PM) affects ~1 in 150 women and ~1 in 470 men in the United States, and can have a significant effect on physical and mental health. Forty percent of males and 16% of female PM carriers are diagnosed with fragile X-associated tremor/ataxia syndrome (FXTAS) between 55-60 years of age, though who will manifest the disease is unknown. FXTAS is characterized by executive dysfunction, gait ataxia, and intention tremor. In the absence of clear markers of disease progression among PM carriers, it is essential to characterize language. Language predicts neurocognitive decline in related conditions (e.g., Alzheimer’s) 10-20 years prior to diagnosis. Language is a promising candidate marker of FXTAS as female PM carriers show age-related changes in pragmatics and lexical-semantics, which have been linked to executive dysfunction. Executive function and language difficulties may adversely impact quality of life. No studies to date have examined language among both male and female PM carriers, limiting our understanding of potential preclinical markers of FXTAS. As a first step, the proposed project will comprehensively examine language among PM carriers in comparison to healthy controls. Without such data, this severely limits our ability to (a) fully understand the impact of the FMR1 PM, (b) examine cognitive correlates implicated in FXTAS (i.e., executive dysfunction), and (c) understand the implications of language use and executive dysfunction on quality of life. This proposal addresses these limitations with three aims: 1) Examine pragmatic and lexical-semantic language among male and female PM carriers in comparison to healthy age- and sex- matched controls; 2) evaluate interactions of age and executive functioning on language; and 3) assess interactions between language and executive function on quality of life. This study will be completed virtually with a cross-sectional sample of 60 PM carriers (30 males, 30 females) without FXTAS and 40 healthy age- and sex-matched controls (20 males, 20 females) between the ages of 35-55. Participants from across the U.S. will be recruited. Participants will complete virtual language elicitation and executive function tasks, and self-report measures of executive function and quality of life. Results from this proposal are expected to inform the nature of language differences among PM carriers compared to controls. It is also expected that age and executive function will interact to adversely influence pragmatic and lexical-semantic language in PM carriers but not controls, which would implicate potential neurocognitive decline. Finally, we anticipate that poorer language and executive functions will adversely affect quality of life among PM carriers. This proposal is consistent with the mission of the National Institutes of Health to enhance health and reduce disability by expanding our understanding of a neurodegenerative condition associated with a common genetic variant,...