Cerebral Amyloid Angiopathy (CAA) and Alzheimer’s Disease (AD) are debilitating diseases that can lead to memory loss, cognitive decline and dementia. A pathological hallmark of CAA and AD is the formation of plaques composed of amyloid-β (Aβ) fibrils in blood vessels and brain. Structural variants of fibrils, termed polymorphs, have been detected in human tissues and are thought to contribute differently to the pathophysiology of these diseases. However, the causal relationship between fibril structure and cellular toxicity remains largely unknown. To evaluate this relationship, we will use novel chemical imaging and electrochemical sensing methods to directly monitor the structural dynamics, aberrant interactions, and toxic activities of different Aβ fibril polymorphs in human tissues and animal models of CAA. Successful completion of this project will ultimately provide information that guides the rational design of drugs to limit the formation and toxic interactions of Aβ fibril polymorphs in people with CAA and AD.