Cholinesterase inhibitors may increase phosphorylated tau in Alzheimer's disease

Cholinesterase inhibitors (ChEIs) are widely used for the symptomatic treatment of Alzheimer's disease (AD). In vitro and in animal studies, ChEIs have been shown to influence the processing of A beta and the phosphorylation of tau, proteins that are the principal constituents of the plaques and neurofibrillary tangles, respectively, in AD brain. However, little is known about the effects of these drugs on A beta and tau pathology in AD. Using avidin-biotin immunohistochemistry and computer-assisted image analysis, we compared A beta and tau loads in the frontal and temporal cortices of 72 brains from matched cohorts of AD patients who had or had not received ChEIs. Patients treated with ChEIs had accumulated significantly more phospho-tau in their cerebral cortex than had untreated patients (P = 0.004). A beta accumulation was reduced but not significantly. These data raise the possibility that increased tau phosphorylation may influence long-term clinical responsiveness to ChEIs.