Systems genetic dissection of brain gene expression reveals excitotoxic mechanisms of Alzheimer's disease.

A causal chain linking AD pathology, transcriptome perturbation, N-Methyl-D-Aspartate receptor excitotoxicity, and neurodegeneration is established, establishing a biphasic model in which early AD pathology activation of a synaptic transcriptional signature that promotes neuronal injury, followed by a decrease that is compensatory.