PROJECT SUMMARY Research. Cardio and cerebrovascular risk factors (CVRFs) such as hypertension and diabetes increase the risk of Alzheimer's disease (AD). The prevalence of CVRFs and dementia are higher among African Americans and Hispanics than Whites. However, the etiological interaction between CVRFs and AD remains unclear. Elucidating how genes and CVRFs interplay to influence AD risk will have the potential to reveal novel molecular targets for prevention strategies and effective treatment for AD. To date, there is no accurate method to identify genes or genetic variants that interact with CVRFs in AD. My overarching goal is to become an independent investigator and interdisciplinary biostatistician on elucidating genetic architecture between AD and CVRFs in diverse race/ethnic populations to aid in diagnosis, prevention, and treatment strategies in AD. The objective of this proposal is to 1) identify genes that interact with CVRFs to confer AD risk and 2) identify epigenomic and transcriptomic signatures that interact with vascular pathologies to confer AD risk and investigate integrated pathways across two omics profiles. The completion of these aims will generate harmonized CVRF data, genes that interact with CVRFs in AD, epigenomic and transcriptomic profiles, and integrative pathways in AD that interacts with vascular pathologies. Our findings will pinpoint the our understanding of the underlying molecular mechanisms of CVRFs, cerebrovascular pathologies, and AD with the potential to reveal novel molecular targets for developing effect drugs for prevention and treatment for AD that can be better tailored to the individual Career development plan. The proposed career development plan will build upon my previous training in statistical genetics and transcriptomics data analysis with the following training goals to enhance my trajectory toward becoming an independent investigator: Training in 1) Clinical, epidemiological, and biological aspects of AD, vascular disease, and aging; 2) Multi-omics Integrative data analysis techniques and interpretation of molecular pathways; and 3) Develop leadership and professional skills to become a NIH-funded independent investigator. To achieve these goals, I have assembled a mentoring and advisory team of internal and external scientists with expertise in Neurology (Dr. Richard Mayeux), Computational Biology (Dr. Yufeng Shen), Bioinformatics (Drs. Badri Vardarajan, Lana Garmire), and Biostatistics (Dr. Iuliana Ionita-Laza). I will broaden my knowledge and proficiency through coursework, workshops, meetings, and hands-on training. Environment. The research environment at Columbia University is ideal for my transition into an independent `big data' AD/CVRFs scientist and a biostatistician. In years 4-5, I plan to develop and submit an R01 to conduct a longitudinal investigation of gene-CVRFs interactions to track progression from CVRFs, vascular pathologies to AD using a multi-omics analysis. Skills and findings from this K01 will be broadly applicable to communities.

PROJECT NARRATIVE Cardio and cerebrovascular risk factors (CVRFs) such as hypertension, diabetes, heart disease, obesity, and stroke increase the risk of Alzheimer's disease (AD). This project uses cutting-edge multi-omics data in humans with advanced statistical methods to identify novel genes that interact with CVRFs in AD using GWAS and to identify epigenomic and transcriptomic profiles, and integrative pathways in AD that interacts with vascular pathologies. My findings may elucidate how genes and CVRFs interplay to influence AD risk, provide insights into the racial/ethnic disparities in AD, suggest personalized strategies for preventing AD in elderly individuals with CVRFs, and reveal novel molecular targets for potential AD treatment.