Since genetic mutations in APP are causal for AD, and abnormal expression of wild-type APP are linked to AD pathology in Down Syndrome patients [130] and early-onset AD with cerebral amyloid angiopathy [131]), it is reasonable to speculate that disturbance of APP-regulated pathways may directly contribute to neuronal and synaptic impairment and disease pathogenesis in an Aβ-dependent or Aβ-independent manner. This evidence concerns the gene APP and Alzheimer disease.