Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD). Hence the maintenance of healthy neurotransmission becomes crucial to slow or halt cognitive decline. In search of identifying proteins that could play a role in synaptic dysfunction, we studied the proteome of a highly vulnerable hippocampal region that is enriched in excitatory synapses. Our in-depth proteomic analysis suggests an impaired presynaptic signaling in AD. Using immunohistochemistry, we verified significantly reduced levels of complexin-1, complexin-2, and synaptogyrin-1 in AD.