Elucidating Molecular Drivers of Aging and Alzheimer's Disease via Multimodal Imaging Mass Spectrometry

PROJECT SUMMARY: The overarching goal of the proposed work is to apply a platform of integrated multiomic imaging modalities and spatially resolved molecular characterization technologies to normal aging and Alzheimer’s disease brain tissues in order to discover and define key molecules and pathways that drive the underlying heterogeneity of the disease. This work will leverage the unique resources of the Mass Spectrometry Research Center and VU Biomolecular Imaging Center, as well as the world-class clinical environment of the Vanderbilt University Medical Center, and the advanced biocomputational infrastructure available through the data analysis laboratories at Vanderbilt University and the Delft University of Technology. The main objectives of our proposed work, which we believe will move the field forward, are to: (1) engage the molecular complexities of Alzheimer’s disease in a new and robust way to create molecular atlases of the heterogenous neuropathologies observed in human brain tissue, (2) define how the molecular underpinnings of neuritic plaques and neurofibrillary tangles overlap with pathways implicated in contributory neuropathologies to inform more precise development of experimental therapies; and (3) deploy multiomic tools to document cell-type specific molecular changes between normal aging and Alzheimer’s disease in well-defined microanatomical regions so changes in the metabolome, lipidome, proteome, and transcriptome can be attributed to the correct cell types and microenvironment. With this suite of technologies, advanced data analysis capabilities, and prior experience in developing atlases of healthy-for-age human tissues, this team will generate datasets with unprecedented detail and the potential to drive molecular discovery. To accomplish these aims, we assembled an interactive and established team of investigators, covering complementary expertise in Alzheimer’s disease, cell biology, analytical chemistry, and data science; and with direct in-house access to advanced instrumentation and facilities. We believe that our spatially resolved and molecularly comprehensive approach will lead to improved mechanistic understanding of Alzheimer’s disease and that these insights could inform better treatment options.