This Project Grant award from the National Institutes of Health's Aging Research program (CFDA 93.866) will support research to identify early transcriptional and pathological changes in brain regions vulnerable to Alzheimer's disease (AD). The $459,076 award, granted to Trustees of Boston University, will use single-nucleus RNA sequencing and targeted mass spectrometry to profile cell type-specific gene expression and tau/amyloid beta proteoforms in the transentorhinal cortex, entorhinal cortex, and prefrontal cortex of pre-symptomatic individuals at early Braak stages. This multimodal analysis aims to reveal the earliest molecular events underlying neurodegeneration in AD. A sub-award to The Washington University will leverage expertise in tau biology and mass spectrometry to quantify specific tau and amyloid species across brain regions and solubility fractions, correlating proteomic changes with the transcriptomic data. The project seeks to uncover genes and pathways driving the selective vulnerability of entorhinal neurons, which exhibit the first signs of pathology in AD.