PROJECT SUMMARY PROJECT 3 Project 3: Comparative Multimodal Phenotypic Characterization of Marmoset Models of AD Alzheimer’s Disease (AD), the most common cause of dementia, is a multifactorial neurodegenerative disorder affecting ~6 million Americans. Currently, there are no interventions capable of preventing, stopping, or treating AD. The scarcity of adequate animal models that enable a comprehensive investigation of the pathogenic mechanisms at play in AD has limited our progress towards discovering effective treatments. There is a critical need for enhanced animal models that incorporate genetic variability, optimal lifespan to support age-related research, superior compatibility as a model of human social and cognitive behavior, and the presentation of AD- related pathology. The central premise of our Consortium “Generation, Characterization, and Validation of Marmoset Models of Alzheimer’s Disease” (MARMO-AD) is that the marmoset will reveal the earliest primate- specific cellular and molecular root causes of AD pathogenesis and progression. We postulate that marmosets engineered to harbor genetic risk variants for early- (EOAD) and late-onset AD (LOAD) will reveal clinical disease trajectories that model those of human AD patients and display primate-specific disease pathogenesis that can be detected with a comprehensive phenotypic characterization pipeline. We hypothesize that: (1) the comprehensive assessment of genetic, molecular, functional, behavioral, and pathological phenotypes in marmosets will provide translatable knowledge of the origins and progression of AD in human populations; and (2) the comparative, longitudinal study of the marmoset LOAD model against the EOAD models and healthy controls will identify emerging phenotypes that precede frank neuropathology and prioritize tractable targets for future therapeutic discovery. The ATP-binding cassette, sub-family A, member 7 (ABCA7) gene was identified by genome-wide association studies (GWAS) as having one of the highest odds ratios for developing LOAD in humans. In this project, we will create a novel genetically engineered marmoset LOAD model incorporating an ABCA7 LOAD variant. Once these animals are born, we will follow them longitudinally to identify emerging phenotypes that deviate from healthy aging ahead of the appearance of frank neuropathology. We will evaluate non-carrier healthy control marmosets to characterize the typical healthy aging trajectory across the lifespan and establish a baseline against which we can contrast our marmoset models of LOAD and EOAD. We will then evaluate the disease trajectory of the ABCA7 marmoset LOAD model relative to the PSEN1 EOAD models via longitudinal, multimodal phenotypic characterization in line with the clinical staging of AD patients. By contrasting our marmoset models of EOAD and LOAD, we hope to identify differential biomarkers of LOAD that can be measured ahead of the emergence of frank neuropathology and prioritize novel targets for therapeutic development. Upon validation of these unique primate AD models, we plan to expand the colony and share this precious resource with the greater AD research community to help accelerate the pace of bringing novel and effective treatments to patients.