Thus, our results lead to a model illustrating that Aβ pathology is at least in part caused by trapping synaptic Zn2+ in Aβ complexes, preventing Zn2+ from reaching its postsynaptic targets like ProSAP/Shank proteins, ultimately leading to a dysregulation of the postsynaptic scaffold and subsequent loss of synapses which might in turn lead to the observed cognitive deficits in AD. Here, SHANK2 is linked to Alzheimer disease.