Alzheimer's disease (AD) is a neurodegenerative disorder characterized by beta-amyloid (AP) deposition, neurofibrillary tangles, neuronal loss, and gliosis. AD is the 6th leading cause of death in the United States and more than 6.2 million Americans suffer from this disease. This year the estimated cost of AD and other dementias is projected to reach $355 billion and can rise to $1 .1 trillion by 2050. The cause of AD remains elusive, and it is likely multifactorial. The greatest risk factors are known to be age, genetics, and inheritance. Despite monumental efforts and vast funding for research, only one therapy has been approved since 2003 and no medication can prevent acquisition of the disease or halt progression. In the last decade more than 200 research projects have not been completed or have failed. More than 15 clinical trials have attempted to promote AP clearance but only one has received controversial approval from the Food and Drug Administration. Most of these studies have treated patients with mild-moderate symptomatic AD, phases by which irreversible damage have already occurred. Therefore, it has been hypothesized that intervention preceding permanent pathological changes could provide better outcomes. However, it is estimated that pathological changes start 15-20 years before the onset of clinical symptoms. Given the extraordinary cost of antibody-based AP, and prolonged treatment periods both primary prevention and tertiary prevention become cost-prohibitive and unsustainable. To develop novel and cost-effective approaches, we have developed phagocytic chimeric antigen receptors (CARs) that can promote stable AP clearance with minimal treatment frequency. Our initial CAR designs promote remarkable induction of potent phagocytosis of oligomeric AP in human microglial cell lines. Using this technology, we propose to design CAR-based cellular therapies to stably promote clearance of AP plaques and prevent further AP deposition. The approach described in this proposal has the potential to be transformative in the treatment of AD and can likely be developed into successful treatments of other protein aggregation diseases of the central nervous system.