Alzheimer’s disease (AD) is characterized by the buildup (accumulation) in the brain of two types of abnormal proteins—amyloid beta, in the form of amyloid plaques, and tau, in the form of neurofibrillary tangles. The accumulation of abnormal tau is thought to cause the death of brain cells directly, but the earliest events that lead to tau accumulation are not well understood. Amyloid beta accumulation is believed to occur before tau, but how the two proteins interact is also not well understood. Many cell and animal models have been created to examine these events, but the data coming from them does not truly represent what happens in the human brain as the models make too much protein too quickly, and it is often not of the type found in the human AD brain. These shortcomings could mislead us on what really happens in the earliest stages of the disease and prevent us from creating the right drugs to prevent the disease from taking off. We have recently developed two sets of tools that can be used to explore the earliest stages of tau and amyloid beta accumulation. The first set of tools are several types of mice that have had their DNA altered so they develop tau pathology (with and without amyloid plaques.) The second is a unique human brain cell model that develops very early tau pathology. Our aims and objectives are to use both models to identify the earliest events that lead to cell dysfunction associated with tau pathology, and examine how the amyloid and tau pathologies interact and drive the disease.