Differential vulnerability of CA1 pyramidal neuron cell types in the 5xFAD Alzheimer's disease mouse model.

Selective neuronal vulnerability is a defining feature of Alzheimer's disease, yet how neurodegeneration unfolds across defined hippocampal CA1 pyramidal neuron populations remains unresolved. Previously, we showed that CA1 pyramidal neurons are organized into molecularly defined laminar cell types that form stable spatial signatures along the longitudinal axis (Pachicano et al., 2025). Here, we investigated how vulnerability manifests across CA1 pyramidal cell types in the 5xFAD mouse model of amyloid pathology. HiPlex single-molecule fluorescence in situ hybridization was used to quantify gene expression at single-cell resolution across hippocampal CA1 subregions across disease progression. Cells were classified into molecularly defined CA1 pyramidal cell types based on marker gene expression, and changes in density, proportion, and molecular state were assessed. Amyloid-associated pathology differentially affected CA1 pyramidal cell types, revealing distinct trajectories of vulnerability and resilience. Specific populations exhibited early and progressive susceptibility, while other populations demonstrated relative preservation across disease timepoints. These effects were consistent across CA1 subregions, indicating that vulnerability follows cell type identity rather than regional anatomy alone. Together, these findings demonstrate that neurodegeneration in Alzheimer's disease is structured by intrinsic cell type identity and provide a cellular framework for understanding selective vulnerability.