The molecular mechanisms that regulate synapse formation have been well documented. However, little is known about the factors that modulate synaptic stability. Synapse loss is an early and invariant feature of neurodegenerative diseases including Alzheimer's (AD) and Parkinson's disease. Notably, in AD the extent of synapse loss correlates with the severity of the disease. Hence, understanding the molecular mechanisms that underlie synaptic maintenance is crucial to reveal potential targets that will allow the development of therapies to protect synapses. Wnts play a central role in the formation and function of neuronal circuits. Moreover, Wnt signaling components are expressed in the adult brain suggesting their role in synaptic maintenance in the adult. Indeed, blockade of Wnts with the Wnt antagonist Dickkopf-1 (Dkk1) causes synapse disassembly in mature hippocampal cells. Dkk1 is elevated in brain biopsies from AD patients and animal models. Consistent with these findings, Amyloid-β (Aβ) oligomers induce the rapid expression of Dkk1. Importantly, Dkk1 neutralizing antibodies protect synapses against Aβ toxicity, indicating that Dkk1 is required for Aβ-mediated synapse loss. In this review, we discuss the role of Wnt signaling in synapse maintenance in the adult brain, particularly in relation to synaptic loss in neurodegenerative diseases.