US-South American Initiative for Genetic-Neural-Behavioral Interactions in Human Neurodegenerative Research

We combine a R01 funding (“US-South American initiative for genetic-neural-behavioral interactions in human neurodegenerative research”, R01 AG057234) with additional support. The R01 project will provide a basic platform anchored in Argentina, Brazil, Colombia, and Peru, that is supplemented with clinical research expertise from the University of California, San Francisco (UCSF) Memory and Aging Center, genomics expertise from the University of California, Santa Barbara, and bioinformatics infrastructure and expertise from Hudson Alpha. This proposal is extended to collaborators in Mexico and Chile. We also will assess novel families across LAC via the Latin America and Caribbean consortium on Dementia (LAC-CD). In addition to the R01 strategy based on patients with familial and sporadic presentations tested for genetic risks (risk scores), it would also support recruitment of AD and FTD families with an autosomal dominant-like presentation from the LAC-CD. This platform will facilitate numerous research projects from additional groups of the LAC-CD; leverage regional expertise in aging and dementia to establish a multidisciplinary, collaborative consortium of diverse, international clinicians and researchers; and promote the development of the next generation of aging and dementia investigators in LAC. In this expanded framework, we would first screen all patients for known AD/FTD/ALS genes and then, for those who screen negative for known genetic causes of disease, we will perform whole-genome sequencing (WGS) for gene discovery. By leveraging the R01 efforts and extending the project scope to include Mexico, Chile, and novel families from LAC-CD, we will establish a network of AD and FTD families and clinicians/researchers, enabling large-scale research to identify novel genetic and SES contributions to AD and FTD in diverse populations. By establishing this collaborative framework, which capitalizes on unique regional populations, our proposal can consolidate a LAC-based platform for future translational research and assessment. Our long-term goal is to identify the unique genetic and SES factors that drive AD and FTD presentation in LAC relative to the US, including risk factors, cognitive profiles and brain imaging. To this end, we will establish a first-in-class cohort anchored in six LAC (Argentina, Chile, Colombia, Brazil, Mexico, and Peru), compared to US samples (totaling > 4200 participants, including 2100 controls, 1050 AD patients, and 1050 FTD patients), led by world-renowned leaders in dementia research. We will couple standardized clinical assessments with innovative analytical techniques to account for heterogeneity in these diverse populations. By combining standardized genetic, neuroimaging, and behavioral (cognitive and SES) measures, we will test the underlying hypothesis that there are unique risk factors for AD and FTD in LAC (e.g., genetic risk factors enriched in LAC populations; underlying cognitive and neural vulnerability due to SES) compared to US populations. Our plan to recruit large numbers of controls and patients across these diverse populations will provide excellent opportunities to identify new genetic and SES risks for AD and FTD. In addition, the machine learning strategies we have developed to reduce the impact of background heterogeneity will allow us to refine the accuracy of our association studies.

USD 2.5MILL, 2019-2024.