APOE and Alzheimer disease: However, in early AD, APOE4 is associated with rapidly increasing tau pathology as the combination of ApoE4 and Aβ pathology induces sufficient degeneration of basal forebrain corticolimbic cholinergic neurons to release the cholinergic “brake” on glial activation in the medial temporal lobe (MTL) and eventually in other cortical regions (Fig. 4).