Project 466732

The role of the FREM3 gene in the human brain is currently not well understood. Initial literature suggests FREM3 is involved in supporting brain structure, and has been implicated in a variety of clinical disorders, including depression and autism. Previous work from our group discovered that FREM3 expression in brain tissue decreases across the normal lifespan. Furthermore, our work identified genetic variants that cause reduced FREM3 expression. In young adults, these variants were associated with reduced activity in age-sensitive brain regions, and decreases in cognitive performance, suggesting lower FREM3 may cause the brain to age faster. However, to test this hypothesis fully, we need to better understand how FREM3 impacts trajectories of structural and cognitive brain aging across the entire lifespan. Furthermore, advancing the currently limited understanding of FREM3s role on a cellular level is necessary to understand the mechanisms by which it affects brain aging. To address these gaps, we propose to use FREM3 variants as a proxy for gene expression in the brain, and evaluate their effect on brain structure assessed via Magnetic Resonance Imaging (MRI), as well as their effect on cognitive performance. Importantly, the data we will use in these analyses will come from participants of different ages, covering the full human lifespan. We also propose to identify other genes that have expression patterns similar to FREM3, and explore the different cellular functions and processes these genes share. These analyses will also use data from young, middle aged, and older adults. Our proposed work will shed light on how the currently poorly understood FREM3 gene affects brain structure and functioning, and explore its emerging role in the aging process.