There is general agreement that beta amyloid (Aβ) is a likely causative agent in the development of Alzheimer’s disease. There is growing evidence that early in the disease an important target of Aβ is the synapse, the site of communication between neurons. We have found that exposure of synapses to Aβ causes synaptic loss. In this proposal we will examine the role played in this process by variant forms of synaptic proteins that have recently been identified by Dr. Tanzi in whole genome analysis of families with late-onset Alzheimer’s disease (LOAD). We hypothesize that the rare variants confer synapses with higher sensitivity to Aβ, thereby facilitating development of AD.