Neurotrophins and synaptic activity work in conjunction during the process of synaptic plasticity. Both are required to stabilize new synaptic structures and the loss of either can lead to cognitive impairments, as new information cannot be stored efficiently or later recalled. Neurotrophins are becoming recognized as mediators of activity-dependent plasticity. The synthesis and release of neurotrophins follow neurosecretory pathways. They are synthesized as immature, pro-neurotrophin molecules, processed, and then mature forms are secreted. These then activate distinct signal tranduction pathways that modify the synapse. High frequency stimulation is known to induce long-term potentiation (LTP) and synaptic enhancement, however, the stability of these changes requires a bi-directional communication between the pre- and post-synaptic terminals and neurotrophins can function in such a capacity. The NGFXAT somatic mosaic murine model demonstrated how neurotrophin and active learning induces a robust synaptic reorganization. Synaptic dysfunction decreases efficient neurotransmission or neurotrophin production and then precedes overt neurodegeneration. The study of synaptic dysfunction and neurotrophin actions with respect to activity will lead to future therapeutic interventions of age-related dementias.