Progression of a typical Neurodegenerative Disease. Alzheimer's disease is used as an example to exhibit the natural progression of a neurodegenerative disease. In the top panel typical magnetic resonance imaging (MRI) scans are shown from a cognitively intact "normal" subject (left), a subject with mild cognitive impairment of the Alzheimer's type (middle), and a patient with AD (right). Note that even the subject with MCI despite displaying minimal symptoms has already clearly lost brain mass and that this increases as the disease progresses. Indeed there is a clear cascade effect in which underlying pathology drives neuronal loss and degeneration leading to clinical symptoms. Based on this one would argue that the optimal time to target the "trigger" of AD would be prior to any signs of damage to the brain or during the initial prodromal phase when pathological changes might be apparent but no clinical signs are yet apparent. Another therapeutic opportunity would be to try to stop the neuronal loss downstream of the initiating pathology.