Project Summary/Abstract The Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE) is a comprehensive prospective cohort study launched at Seoul National University (SNU) in 2014 using a similar design and methods as the North American Alzheimer’s Disease Neuroimaging Initiative (ADNI). The KBASE cohort consists of well-characterized participants including cognitively normal (CN) controls with a wide age range (20 to 90 years), mild cognitive impairment (MCI) and AD dementia (AD). A unique aspect of KBASE is the systematic longitudinal collection of comprehensive clinical, cognitive and lifestyle data, multimodal neuroimaging (MRI/MRA, DTI, rsfMRI, amyloid, tau and FDG PET), and bio-specimens in Korea for the first five years (“KBASE1”). Some KBASE data have been analyzed and reported but much of the extensive KBASE data set and samples await comprehensive analysis. The proposed project (“KBASE2”) represents a collaboration between the NIA Alzheimer’s Disease Sequencing Project (ADSP) and partners, Indiana University (ADNI Genetics Core, Indiana NIA-designated ADRC, and IU Network Science Institute), the KBASE team at SNU in Korea, University of Southern California (USC), and the University of Pennsylvania. Over 1000 whole genome sequences (WGS) of Korean participants will be contributed to the ADSP, and the extensive ADSP multi-ethnic data set will be analyzed. WGS data will be harmonized by the NIA Genetics and Genomics Center for AD (GCAD) and shared via the NIA Genetics of AD Data Storage Site (NIAGADS). The Laboratory of Neuroimaging (LONI) at USC will support sharing of MRI and PET and related endophenotypes, as it does for ADNI. KBASE2 will continue longitudinal data and sample collection and provide high throughput WGS and RNA-Seq as well as data harmonization and sharing (Aim 1), perform intensive brain network-based analyses of longitudinal amyloid, tau, neurodegeneration and vascular (A/T/N/V) imaging biomarkers in relation to clinical data (Aim 2), employ integrative systems biology and functional genomics methods to analyze multi-omics data for association with A/T/N/V biomarkers for AD, and provide new insight into AD biomarker-related dysregulated gene modules and pathways (Aim 3). The overarching concepts driving this multidisciplinary international collaborative project are that 1) development of precision medicine for AD and related disorders (ADRD) requires systematic multi-modal biomarker collection in diverse cohorts during early at-risk stages of disease to identify robust diagnostic, prognostic and therapeutic targets and 2) sophisticated analytic strategies that address the complexity of multi- layer multimodal data and heterogeneous and diverse participant cohorts are essential. We hypothesize that integrative longitudinal analysis of genetic and -omics networks with structural and functional brain networks will yield new diagnostic and treatment-relevant insights related to A/T/N/V and other aging...