PROJECT 3: PROJECT SUMMARY/ABSTRACT Cerebral amyloid angiopathy (CAA) is an age-associated vasculopathy in which there is deposition of amyloid-β protein in the walls of leptomeningeal and parenchymal blood vessels. It can be seen in association with Alzheimer’s disease- neuropathologic change (AD-NC), as well as in isolation. In this study, we focus on how CAA alters the local cellular environment in three distinct regions of the brain that are known to have variable susceptibility to CAA: superior temporal gyrus, dorsolateral prefrontal cortex, and calcarine cortex. We will compare CAA in isolation and in association with increasing burden of AD-NC. There is extremely limited molecular data on how CAA can modify the local cellular environment in aging, although we know CAA can cause cognitive decline in the absence of any other proteinopathy, but can also exacerbate the cognitive decline with proteinopathy. Thus, the overarching goal of this project is to generate a spatial atlas of cell types and molecular signatures in cases with CAA and variable severities of Alzheimer’s Disease- Neuropathologic Change (AD-NC) to assess short- and long-range, and interactive effects of multiple pathologies on cellular composition and signatures from post-mortem human brain tissue. We hypothesize that CAA has local effects on the cell type composition and protein signature nearby, affecting all elements of the neurovascular unit (NVU), and that the effects of CAA are exacerbated by the presence of comorbid AD proteinopathies. For this project we propose a combination of novel but demonstrably scalable protein and gene expression approaches, to study large volumes (300-micron thickness) of human tissue with combinations of CAA with and without AD-NC. This will allow for the generation of a high-resolution atlas of cell types and gene expression signatures in aged human brain tissue that relate to CAA, complementing many of the existing and ongoing bulk and single-nucleus RNA-seq studies in the field of human neurodegeneration research