Dr. Therrien’s project examines how inherited genetic risk for Alzheimer’s disease (AD) shapes the brain’s immune response to inflammation originating outside the brain. Peripheral infections can trigger inflammatory cytokines in the bloodstream that influence microglia—even when the infectious agent itself does not enter the brain—potentially pushing these cells into dysfunctional or maladaptive states. While prior studies have focused on single risk genes such as APOE, this project takes a broader view, examining how overall genetic susceptibility modifies immune responses.
The central hypothesis is that Alzheimer’s genetic risk alters how microglia respond to inflammatory cytokines, thereby reshaping antigen-presentation pathways and promoting harmful interactions with astrocytes, neurons, and infiltrating T cells.
To address this, the team will identify which inflammatory cytokines most strongly disrupt microglial function and determine how these responses vary by genetic background, including APOE genotype and broader polygenic risk. They will define how APOE genotype influences microglial antigen-presentation programs and assess the downstream impact on astrocytes and neurons using human brain organoid systems. Finally, they will determine whether amyloid-exposed microglia activate CD4 T cells in an APOE- and HLA-dependent manner, thereby linking genetic risk to adaptive immune engagement.
Through collaboration with other laboratories of the Neuroimmune consortium, the Therrien team will integrate antigen-presentation datasets with astrocyte–T cell interaction models, border macrophage platforms, and in vivo amyloid models to validate disease-relevant immune pathways. By clarifying how inherited risk converges with inflammatory signaling, this work aims to identify genetically informed therapeutic strategies that could reduce maladaptive neuroimmune communication in AD.
