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.