Project 1: Identification of Early Life molecular determinants of Alzheimer's Disease pathogenesis

PROJECT SUMMARY PROJECT 1 The overarching aims of this proposal are to identify the initial cascade of events that drive the inception and progression of Alzheimer’s Disease (AD). There is an urgent need to prevent, and treat AD. We hypothesize that genetic risk for AD confers disease pathogenesis in early life that will be detected by studying molecular and cellular events before the age of adolescence which will inform prevention. By employing a model system that more faithfully recapitulates the genetic, molecular, cellular, physiological, anatomical and structural organization of the primate brain, we will be able to identify underlying drivers of AD and better model disease pathogenesis and progression in order to prevent disease. In support of these goals, this project (Project 1) aims to identify the early life primate-specific molecular determinants of Alzheimer’s disease emergence and progression using marmosets genetically engineered with the presenilin 1 (PSEN1) risk variant, an early onset AD mutation. The PSEN1 marmoset models provide the ability to evaluate divergent changes at the molecular, cellular, and systems level from birth through infancy, adolescence, and aging. The Specific Aims of this project are: 1) to evaluate the disease trajectory of PSEN1 mutant marmosets relative to healthy age-matched and normal aged controls using established and emerging AD biomarkers; 2) to conduct comprehensive behavioral characterization of the PSEN1 marmoset models relative to healthy controls via longitudinal multimodal phenotypic characterization from neurodevelopment through lifespan; and 3) investigate the molecular signatures of neuronal cells derived from fibroblasts as a surrogate to brain. Through these specific aims, we expect to have comprehensively characterized the first genetically engineered marmoset models of AD that recapitulates the spectrum of AD-related phenotypes observed in AD patients for behavioral, cognitive, biomarker, and neuropathological hallmarks using translational approaches; identified early molecular changes at the cellular level using multi-omics approaches prior to the emergence of frank AD neuropathology and cognitive decline; and created the foundation of knowledge for the utility of genetically engineered marmosets with AD risk variants as validated models.