Sleep duration Polygenic Risk Score: Association with cognition and brain measures

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PROJECT SUMMARY/ABSTRACT Sleep is a vital indicator of overall health and well-being, and serves many functions including essential roles underlying cognitive processing. Changes in sleep are common among cognitively healthy individuals and those with neurodegenerations such as Alzheimer’s disease dementia (AD)[1-4]. Thus, sleep disturbances have been characterized as significant risk factors for cognitive decline and incident AD[5-8]. More specifically, short sleep duration has been linked to poor cognitive performance and greater cortical β-amyloid (Aβ) burden, a precursor to cognitive decline/ dementia[9-11]. Furthermore, genomic variability has been also reported as a significant contributor to cognitive function and neurodegenerative disorders[12-16]. Polygenic Risk Scores (PRS) have been improving over the last years to provide a better assessment of disease risk predictions[17]. PRSs developed to assess risk of AD were reported as significant predictors of cognition and different sleep measures in elderly and in youth [18]. We recently showed preliminary data regarding the association between sleep-based PRS (Sleep PRS) and cognition[19]. There is also reported evidence of an association between sleep and brain structure[20-22], however, the majority of studies examine individual brain measures. Despite work exploring the association between sleep and cognition, research on the link among sleep, sleep genetics and cognition in cognitively healthy adults across the age range remains sparse. The current proposal aims to investigate the association between a Sleep PRS, summarizing the genetic contribution to sleep duration[23-26], with cognition, and the role of brain measures to this association. The analytical sample will consist of ~1900 cognitively healthy adults (20-80 y.o.) drawn from two cohorts; the Reference Abilities Neural Networks/Cognitive Reserve (RANN/CR), and the Washington Heights-Inwood Columbia Aging Project (WHICAP). The specific aims are to: a) characterize the association between Sleep PRS and cognition both cross-sectionally and longitudinally, b) identify how brain measures might mediate these associations, and c) expand the work by creating a Cognitive PRS, evaluating it in a similar manner, and examining overlap with the Sleep PRS. This K99/R00 application presents a program that will support the applicant on a path towards becoming an independent investigator focused on characterizing the association between genetics and cognition, while examining the role of brain measures in this association. The activities in this application are set in a resource- rich environment that will provide the applicant with new skills, deepening, and strengthen her expertise in: 1) genetics, 2) neuroimaging, 3) cross-sectional and longitudinal analyses of cognitive behavior data, and 4) the responsible conduct of research. The combination of the environment at Columbia University, training plan, and mentorship team will not only provide the candidate with a spectrum of new methods and skills that will establish her as an independent research scientist, but will also produce a body of knowledge that will clarify how sleep genetics are associated with cognition in cognitively healthy participants across the adult age-range.