Sex differences in the genetic etiology of cognitive resilience to Alzheimer's disease

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PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder marked by hallmark pathologies, amyloid plaques, and neurofibrillary tangles, leading to downstream consequences including neurodegeneration and cognitive impairment. However, 30% of elderly adults are cognitively resilient to AD, presenting with AD pathology yet never presenting with downstream consequences. Applying the cognitive resilience framework to genetic studies has resulted in the identification of novel genetic loci that differ from known AD genetic loci. However, to date, the cognitive resilience framework has yet to be explored in a sex- specific manner. Sex differences in AD pathogenesis are well-established, with growing evidence suggesting genetic factors may contribute to these differences. Thus, this F31 proposal will investigate sex differences in the genetic etiology of cognitive resilience to AD. We will leverage cognitive, biomarker, and genetic data from eleven well-characterized cohorts of cognitive aging. To build robust cognitive resilience phenotypes, we will implement latent variable modeling, and then perform a series of sex-aware genomic analyses on the resulting phenotypes. First, we will perform sex-stratified and sex-interaction genome-wide association studies (GWAS), followed by gene-level tests, including applying sex-specific predicted gene expression models. Second, we will perform X-wide association studies (XWAS). To date, there have been no XWAS on AD cognitive phenotypes, due to the X-chromosome’s additional challenges arising from dosage differences between sexes. To this end, we will apply genetic pipelines tailored for the X-chromosome to allow for its inclusion. Third, we will perform genetic correlation tests with the aforementioned GWAS and XWAS and a unique resource of thousands of sex-stratified GWAS summary statistics on health-related traits from the UK Biobank. These tests will identify shared genetic architecture between cognitive resilience and other complex traits, pointing to possible sex-specific biological pathways driving cognitive resilience. Overall, the proposed research aims will identify novel genetic loci, candidate genes, and molecular pathways associated with cognitive resilience to AD pathogenesis in a sex-specific manner. To complete all aims, this F31 proposal will leverage cutting-edge resources and the collaborative environment of the Vanderbilt Memory & Alzheimer’s Center. The candidate, Jaclyn Eissman, will independently complete all statistical analyses with guidance from an expert mentorship team. This team has expertise in computational genomics, clinical and biomarker contributions to AD, and sex- aware genetic models of complex traits. The outlined research aims along with the detailed and parallel training plan will allow the candidate to have the skills to successfully complete the proposed research aims and enhance her professional development skills in preparation for a career in science. Findings from this F31 proposal will contribute to revealing novel insight into AD progression and to identifying novel therapeutic targets that best suit an individual based on their genetic context and biological sex.