Title:Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in
Alzheimer’s Disease: Nexus of Cholinergic and Nerve Growth Factor Dysfunction
Volume: 18
Issue: 13
Author(s): Donald E. Moss*Ruth G. Perez
Affiliation:
- Department of Psychology, University of Texas at El Paso, El Paso, Texas 79968, USA
Keywords:
Alzheimer’s, acetylcholinesterase, EC 3.1.1.7, butyrylcholinesterase, EC 3.1.1.8, nerve growth factor, anticholinergic, acetylcholinesterase inhibitor, tauopathy
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is increasingly
viewed as a complex multi-dimensional disease without effective treatments. Recent randomized,
placebo-controlled studies have shown volume losses of ~0.7% and ~3.5% per year, respectively,
in the basal cholinergic forebrain (CBF) and hippocampus in untreated suspected prodromal
AD. One year of donepezil treatment reduced these annualized rates of atrophy to about
half of untreated rates. Similar positive although variable results have also been found in volumetric
measurements of the cortex and whole brain in patients with mild cognitive impairment as well
as more advanced AD stages after treatments with all three currently available acetylcholinesterase
(AChE) inhibitors (donepezil, rivastigmine, and galantamine). Here we review the anti-neurodegenerative
benefits of AChE inhibitors and the expected parallel disease-accelerating impairments
caused by anticholinergics, within a framework of the cholinergic hypothesis of AD and AD-associated
loss of nerve growth factor (NGF). Consistent with the “loss of trophic factor hypothesis of
AD,” we propose that AChE inhibitors enhance acetylcholine-dependent release and uptake of
NGF, thereby sustaining cholinergic neuronal viability and thus slowing AD-associated degeneration
of the CBF, to ultimately delay dementia progression. We propose that improved cholinergic
therapies for AD started early in asymptomatic persons, especially those with risk factors, will delay
the onset, progression, or emergence of dementia. The currently available competitive and pseudo-
irreversible AChE inhibitors are not CNS-selective and thus induce gastrointestinal toxicity that
limits cortical AChE inhibition to ~30% (ranges from 19% to 41%) as measured by in vivo PET
studies in patients undergoing therapy. These levels of inhibition are marginal relative to what is required
for effective symptomatic treatment of dementia or slowing AD-associated neurodegeneration.
In contrast, because of the inherently slow de novo synthesis of AChE in the CNS (about one--
tenth the rate of synthesis in peripheral tissues), irreversible AChE inhibitors produce significantly
higher levels of inhibition in the CNS than in peripheral tissues. For example, methanesulfonyl fluoride,
an irreversible inhibitor reduces CNS AChE activity by ~68% in patients undergoing therapy
and ~80% in cortical biopsies of non-human primates. The full therapeutic benefits of AChE inhibitors,
whether for symptomatic treatment of dementia or disease-slowing, thus would benefit by producing
high levels of CNS inhibition. One way to obtain such higher levels of CNS AChE inhibition
would be by using irreversible inhibitors.
