Fig. 4

Amyloid pathology facilitating phenotype of early AD exemplified by APOE4 homozygotes with BCHE-K aged < 75 years. In preclinical and prodromal AD, especially in APOE4 homozygote BCHE-K carriers below 75 years of age, lower BuChE activity results in higher extracellular ACh and increased signaling through nAChR on glial cells (1). “Functionally underactive” glia with decreased phagocytic, degradative functions, and homeostatic responsiveness (2), impair Aβ clearance resulting in earlier and greater amyloid accumulation (3). In early AD, limbic cholinergic denervation due to ApoE4, Aβ, and tau-mediated damage to basal forebrain cholinergic neurons that project to corticolimbic regions, removes the cholinergic “brake” on glia to increase glial activation, tau pathology and neurodegeneration in the MTL (4). The spread of this pathology outside of the MTL is initially limited until cholinergic denervation has progressed to include other neocortical areas (5). Thus, high levels of amyloid accumulation develop at a younger age, and basal forebrain cholinergic denervation of MTL structures results in hippocampal atrophy and a rapidly progressing limbic-amnestic presentation in early AD with good response to AChE-Is (6). The progression of corticolimbic cholinergic denervation to neocortical areas beyond the MTL results in the spread of glial activation, tau pathology, and neurodegeneration