ISR Awards

Examining Sex Differences in Pleiotropic Effects for Depression and Alzheimer?s Disease Across the Life Course

Alzheimer?s disease and its related dementias (ADRD) are debilitating neurodegenerative diseases that can lead to memory loss, cognitive deficits, and behavioral changes. As nearly two-thirds of persons diagnosed with Alzheimer?s disease are women more research is needed to understand sex differences in the biological mechanisms that underpin AD. Although depression has been identified as a premorbid risk factor for AD and poor cognitive function, higher rates of depression among women than men suggest that depression-related phenotypes and underlying biological factors may contribute to sex differences in ADRD and cognitive functioning. Characterizing the genetic risk for complex disorders such as ADRD and depression has proven difficult. While certain genetic loci such as the APOE/TOMM40 region on chromosome 19 and genes in the hypothalamic pituitary adrenal axis have been implicated for ADRD and depression, respectively, it remains to be seen if there is further independent, cumulative genetic risk beyond these regions. Furthermore, we have not yet fully explored if shared genetic risk (pleiotropy) for these phenotypes interact with environments to lead to pronounced sex-differences in older populations. The proposed pilot project will implement two statistical aggregation techniques?polygenic scores (PGSs) and gene region analyses?to assess the degree of sex-specific pleiotropy between depression and AD in the Health and Retirement Study (N~10,000). Moreover, we will exploit longitudinal data from the Fragile Families and Child Wellbeing Study (N~2000) to evaluate sex differences in the temporal associations between depression and cognitive function as well as pleiotropic predictors of these processes. As depression and related neuropsychiatric symptoms are important predictors of heterogeneity in dimensions of AD and cognitive function, this project is a critical extension of our previous work that examined only sex differences in psychiatric comorbidity. This research will help to improve our understanding of sex differences in AD and cognition across the life course and may have important implications for early identification of high risk groups, treatment approaches, and quality of life.