The cholinergic hypothesis is the oldest theory underlying AD pathogenesis and builds off the observation that choline acetyltransferase (ChAT) activity is greatly reduced at synapses in the amygdala, hippocampus, and cortex of AD brains,40, 41, 42, 43 resulting in a corresponding cholinergic failure and impairment of memory, attention, and learning.44, 45. This evidence concerns the gene CHAT and Alzheimer disease.