Synaptic damage is an early pathological event common to many neurodegenerative disorders such as Alzheimer's disease (AD) and is the best correlate to the cognitive impairment. Several molecules involved in AD and in other neurodegenerative disorders play an important role in synaptic function and when misfolded aggregate and form amyloid fibrils. Synaptic proteins with an amyloid domain include amyloid beta-protein precursor, prion protein, huntingtin, ataxin-1 and alpha-synuclein. Two of the possible mechanisms by which alterations in synaptic proteins lead to synapse damage are: 1) misfolded or aggregated synaptic molecules have lost their normal function and/or 2) they have gained a toxic capacity. Recent studies support the possibility that while oligomers are toxic, polymers might be inactive. The mechanisms by which oligomers trigger synapse loss could be related to their ability to triggers stress signals once they enter the nucleus and/or accumulate at the endoplasmic reticulum.