Alzheimer’s disease is caused by the accumulation of toxic protein aggregates in the form of extracellular amyloid plaques and intracellular tangles composed of the tau protein. In the current genomic era, several genes have been discovered that are associated with Alzheimer’s disease risk. However, for most of these risk genes, we do not know in any detail how they are playing a role in the development of Alzheimer’s disease. One of the top genes to emerge from these genetic studies is the Clusterin (CLU) gene. Our lab recently has published that CLU plays a critical role in the formation of the extracellular amyloid plaques that form near neurons and also the blood vessels of the brain. We now have new evidence that CLU also might play a role in the formation of the other major pathological hallmark of Alzheimer’s disease, the neurofibrillary tau tangles. In this proposal, we will directly test whether CLU influences the ability of the tau protein to accumulate and cause toxicity and behavioral impairments using novel mouse models developed in our lab. We also will employ new cutting-edge technologies to determine how CLU influences tau pathology. The completion of these studies could firmly establish that CLU is an important therapeutic target for the development of both major Alzheimer’s disease pathologies.