Abstract: Alzheimer?s Disease (AD) is thought to be caused by a combination of multiple genetic and environmental factors, and the role of infectious agents has been debated for decades. A recent multi-omic, epidemiological study of large Alzheimer patient cohorts revealed a specific and significant association of human herpesvirus 6A (HHV6A) with AD. However, these studies could not resolve which HHV6A specific genes were involved or how HHV6A might affect cells of the central nervous system (CNS) to exacerbate AD. As HHV6A is mainly present in the brain in its latent form, we asked the question of whether the major latency associated gene U94A, affects host cells functions that are relevant to Alzheimer disease pathology. Using a human cell system, we found that U94A expression impairs the migration and maturation of human glial progenitor cells (OPCs) and leads to synapse loss in human neurons. Preliminary transcriptomic and proteomic analysis of U94A infected cells showed dysregulation of genes involved in cytoskeletal functions and synaptic maturation. In addition, we found that expression of U94A increases accumulation of A? and phosphorylation of Tau in cells co-expressing a familial Alzheimer disease (FAD)-linked, mutant APPswe variant. These phenotypes are particularly relevant for the early stages of Alzheimer disease, as mounting evidence suggests that synapse and neurite loss, associated with diffuse demyelination precede cognitive impairment. Based on our published and preliminary data, we propose that the latency gene U94A represents a disease-modifying factor that renders neural cells vulnerable to Alzheimer disease associated risk factors, and exacerbates Alzheimer?s pathology in vitro and in vivo. We propose three Aims in which we test the hypotheses that (i) U94A expression exacerbates A? accumulation in iPSC derived neural cells from familial Alzheimer disease (FAD) patients and will exacerbate neuronal and glial cell impairments, (ii) that U94A expression in the context of FAD mutations in mice will exacerbate cellular pathologies in vivo and (iii) that the cellular impairments caused by U94A are sufficient to exacerbate cognitive deficits in familial Alzheimer?s mouse models. This work will provide insight into the potential role of infectious agents in Alzheimer?s pathology and will establish that HHV6A viral latency is not merely a benign state of viral infection, but an important disease modifying factor.