The distinct effects of acetylcholinesterase inhibitor treatment on RUN- and QW-associated aberrant calcium activity of APP/PS1 mice suggest that the therapeutic actions of acetylcholinesterase inhibitors in AD may require theta-dependent brain states (i.e., RUN and REM sleep) associated with high cholinergic activity, and we anticipate that physostigmine’s actions reflected in the partial rescue of both hippocampal neuronal activity and theta–gamma PAC are likely to contribute to the therapeutic benefit of acetylcholinesterase inhibitors in AD. This evidence concerns the gene APP and Alzheimer disease.