Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to dramatic effects on the affected individuals and their families. While the characterization of the genetic contribution to AD and underlying molecular mechanisms has advanced the understanding of the disease in recent years, studies have failed to find definitive mechanisms that account for disease progression. The influence of pathogens on AD potentially mediates an environmental impact on the established genetic contributions to AD. Here, we directly dissect the contribution of pathogen-related effects down to the cell-type-specific molecular basis by systematic profiling, computational integration, and experimental validation of the transcriptional signatures across individuals, brain regions, and cell types. In Aim 1, we use scRNA-seq in human, mouse, and human iPSC brain organoid samples of AD that are infected with Herpes Simplex Virus 1 or Cytomegalovirus (HSV-1/CMV) to generate millions of single- cell (sc) level maps with the end goal of a transcriptional atlas. In Aim 2, we analyze the resulting datasets and underlying molecular mechanisms, enabling us to discover and converge genes, pathways, cell types, and brain regions to functional and causal mechanisms that drive pathogen-related alterations. In Aim 3, we use our well-established iPSC model to test our predicted mechanisms with both high-throughput and cell-type specific assays. The resulting datasets, computational predictions, and experimentally-supported mechanisms will shed light on the pathogen-related influences on AD pathology and will help deepen our understanding of the disease in general as we develop more personalized therapeutic approaches to treating AD.

Narrative: Alzheimer’s Disease is a devastating neurodegenerative disease, the most common cause of dementia, and a significant healthcare burden worldwide, with many complex genetic and environmental drivers that remain uncharacterized. Pathogenic infections have been proposed as a potential risk factor for Alzheimer's, by triggering an immune response utilizing Amyloid beta as antimicrobial peptides, which protect against infections in the short term, but ultimately cause excessive Aβ deposition and the pathological cascades that ultimately lead to dementia, a link particularly relevant given the Covid-19 pandemic. Here, we dissect the potential mechanistic basis of such pathogen-Alzheimer's interactions using cutting-edge experimental and computational methods, and focusing on HSV-1 and CMV infections as a model for Alzheimer's-pathogen interactions in hopes for this to provide a foundation for both a deeper understanding of how pathogens impact Alzheimer's and the development of new therapeutics against this devastating disorder.