Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. We have known for many years that the proteins amyloid beta and tau clump abnormally in plaques and tangles in the brains of people with Alzheimer’s disease. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However, the cascade leading from changes in amyloid to widespread tau protein pathology and brain cell death remain unclear. Loss of connections between brain cells called synapses is the best marker in the brain of the symptoms of Alzheimer’s disease including memory and thinking problems. In this project, we are testing the idea that the brain changes in Alzheimer’s disease leading from amyloid beta to tau to brain cell death and dementia symptoms begin in synapses. The team is using cutting edge imaging technology to examine synapses in human brain samples from people who died with Alzheimer’s disease and in models of disease. We are asking 3 main questions (1) Do amyloid and tau clump abnormally in synapses in human Alzheimer’s disease brain where they may be working together to cause brain damage? (2) In a new mouse model of Alzheimer’s can we better understand how amyloid beta and tau cooperate to damage synapses and can we recover brain function by lowering tau levels? (3) Can we use human stem cell derived neurons to learn more about how amyloid beta and tau work together to cause synapse loss? Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.