Project 3: Novel Mechanisms PROJECT SUMMARY/ABSTRACT Recently, significant progress has been made in understanding the trajectory of amyloid and tau changes in both late-onset (LOAD) and autosomal-dominant AD (ADAD), clearly establishing a long preclinical stage during which pathologies develop prior to symptoms. While these two forms of AD share many fundamental pathological and clinical features, ADAD is mechanistically distinct, with mutations resulting in overproduction of β-amyloid in addition to impaired clearance as is found in LOAD. Since both forms of AD are complex and heterogeneous, a more complete understanding of AD is necessary to accelerate progress towards a cure. Challenges now remain to unravel the processes that initiate and promulgate disease and to assess their potential as novel therapeutic targets and biomarkers. In particular, there is an urgent need to better understand other molecular processes tracking early triggers of neurodegeneration, such as neuro- inflammation and synaptic injury and their associated biomarkers that herald disease progression. The Accelerating Medicines Partnership for Alzheimer’s disease (AMP-AD) consortium has identified molecular networks and novel target biomarkers (including those involved in neurinflammation and synaptic injury) in post-mortem LOAD brain tissue. However, the understanding of the role of APP, PSEN1 and PSEN2 in ADAD pathogenesis and downstream mechanisms remains limited. The goal of Project 3 is to use systems-based approaches to define the impact of ADAD mutations and neuroinflammatory and synaptic networks on disease progression in participants in the Dominantly Inherited Alzheimer network (DIAN), which will, in turn, identify novel disease biomarkers. We hypothesize that neuroinflammatory processes in ADAD, as defined by direct molecular analysis of ADAD brain and detected in living individuals by their associated fluid biomarkers, are altered early in the natural course of disease and impact progressive neuronal injury and cognitive decline. In Aim 1, we will use “-omics” and systems biology approaches (with molecular profiling via transcriptomics and mass spectrometry [MS]-based proteomics) to define the inflammatory and synaptic networks that are dysregulated in ADAD brains. Paired with network data derived from mutation carriers and isogenic control induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, and microglia, we will create a systematic molecular interaction map to elucidate connections between ADAD mutations, inflammation, synaptic function, and associated therapeutic targets. In order to translate AD brain network information into applications that have potential clinical relevance and utility, in Aim 2, CSF obtained longitudinally from DIAN participants will be interrogated by MS and immunoassays for proteins revealed in Aim 1, along with several “emerging” biomarkers of neuroinflammation (YKL-40, sTREM2, and progranulin) and synaptic injury (VIL...