OBJECTIVE

We tested the premise that cholinesterase inhibitor therapy should target butyrylcholinesterase (BuChE) in Alzheimer's disease (AD), not acetylcholinesterase (AChE) alone, because both enzymes hydrolyze acetylcholine, and BuChE is increased in AD cerebral cortex.

METHODS

To examine this issue in vivo, we quantified human cerebral cortical BuChE activity using tracer kinetic estimates (k(3)) of 1-[(11)C]methyl-4-piperidinyl n-butyrate ([(11)C]BMP) hydrolysis determined by positron emission tomography. Validation of the putative positron emission tomography method included regional distribution, positive correlation with age, and attenuation by the nonselective cholinesterase inhibitor physostigmine, but no attenuation by the AChE-selective inhibitor donepezil. Positron emission tomography scans in AD patients (n = 15) and control subjects (n = 12) measured both BuChE (using [(11)C]BMP) and AChE activity (using N-[(11)C] methylpiperidin-4-yl propionate, an established method).

RESULTS

As expected, AChE activity in AD cerebral cortex was decreased to 75 +/- 13% of normal (p = 0.00001). Contrary to prediction, accompanying BuChE activity also was decreased to 82 +/- 14% of normal (p = 0.001).

INTERPRETATION

Failure to observe increased [(11)C]BMP hydrolysis in vivo makes it less likely that incremental BuChE contributes importantly to acetylcholine hydrolysis in AD. The findings do not support the premise that inhibitor therapy should target BuChE so as to prevent increased levels of BuChE from hydrolyzing acetylcholine in AD cerebral cortex.