Dr. Orr’s team is using spatial proteomic profiling to analyze individual neurons from 180 postmortem brain samples from adults aged 20 to 90+. Their goal is to identify the molecular features that distinguish healthy aging from pathogenic aging. They have discovered distinct, nonlinear age-related protein signatures that reveal two separate processes: general aging patterns associated with non-pathogenic forms of amyloid beta and tau, and disease-related trajectories involving aggregation-prone amyloid beta and phospho-tau. These findings suggest that normal brain aging and pathogenic aging follow fundamentally different molecular pathways.
Building on these findings, they hypothesize that neurons from individuals with autosomal dominant AD (ADAD) exhibit signatures of advanced, pathogenic aging, whereas neurons from healthy centenarians reflect delayed or resilient biological aging. In Aim 1, they will compare the proteins found in neurons from ADAD brains to those from normal agers and late-onset AD patients. In Aim 2, they will profile brains from cognitively intact centenarians to assess whether they maintain a biologically younger neuronal profile. The team will use data analysis tools to see where these samples fall within typical patterns of brain aging. By integrating spatial proteomic data with clinical, genetic, and pathological information—and complementing with multi-omic data from neuronal cultures, choroid plexus, cerebrospinal fluid, and lipidomics—the team will create a comprehensive systems-level view of neuronal aging, vulnerability, and resilience. They will share validated protein signatures with the CureAlz Brain Aging Consortium for independent validation and collaborate with other consortium labs for cross-platform integration, mechanistic follow-up, and functional studies.
