Alzheimer ‘s disease (AD) affects millions of Americans and causes significant morbidity and mortality. Although genetic determinants of AD have been a major focus of research over the last three decades, there is limited insight into co-factors that contribute to AD pathology and progression. Recent genetic associations implicating alterations in innate immunity to risk for AD, suggest that environmental factors, such as infection, may modulate brain immune function and could also play a role in AD. Previous studies have suggested that chronic infection of neurotropic herpesviruses could be one factor that contributes to the development of AD pathology. In particular, herpes simplex virus type 1 (HSV-1) DNA has been found in AD brains and in β-amyloid plaques. Through careful multiscale network analysis of the large RNA-seq. datasets within the Accelerating Medicines Partnership-AD (AMP-AD) consortium, we have observed an increased abundance of transcripts derived from several herpesvirus family members across multiple brain regions from subjects with AD, and we have found that HSV-1 expression was associated with the clinical dementia score of AD patients. Notably, this observation has been replicated across three independent AMP- AD RNA-seq studies. We found evidence of viral mimicry upon viewing our viral/AD-associated genes through the lens of transcriptional regulatory networks. We have identified candidate transcription factors and their downstream targets associated with viral expression, as well as kinases that regulate activity of those transcription factors. Additionally, HSV-1 transcripts were associated with increased expression of several key regulators of APP processing. This project is a collaboration with Martin Darvis and Christine Johnston at the University of Washington to explore this provocative transcriptomic data using a set of experiments to determine if expression of herpesviruses encoded proteins and HSV-1 infection contribute to the development and progression of AD. We hypothesize that neurotropic herpesvirus infection alters transcriptional regulatory networks of known AD genes to drive pathology. Two parallel lines of investigation are being conducted. The first combines the experience of the multidisciplinary team with neuropathology, HSV-1 biology, HSV infection in mice and RNA-seq analysis to directly ask (1) whether active viral infection with HSV-1 can alter pathology in AD mouse models, and (2) whether there longitudinal changes in AD-relevant RNA expression in HSV-1 infected AD mice. Through our comparative approach and computational modeling, we are characterizing how HSV-1 infection impacts known AD pathways and neuropathological features. The second leverages the use of adeno-associated viral vectors to express candidate transcription factors identified in AMP-AD RNA-seq studies in brain slice cultures and mouse models of AD pathology. As a result, we are establishing new models and a testing procedure including ex vivo and in vivo models that allow us to explore our provocative RNA-seq AMP-AD data in way that could rapidly inform a novel anti-viral based therapeutic approach to AD.