But a study released last year concluded that the compounds could actually worsen the other major component of Alzheimer's pathology: neurofibrillatory tangling.
Frank LaFerla, Ph.D., and colleagues administered daily nicotine to mice genetically engineered to develop amyloid β plaques and neurofibrillatory tangling. After 5 months, their brains showed significant accumulation of tau in pyramidal neurons–a preliminary event in tangle formation–and significant increases in phosphorylated tau, a protein found in the tangles (PNAS 2005;102:3046–51).
“That doesn't mean that there isn't a place for NRAs,” said Dr. LaFerla, codirector of the Institute for Brain Aging and Dementia at the University of California, Irvine. “Nicotine is a pretty dirty drug and probably has other effects than just binding to the receptor. If you could come up with a more selective compound, you might still see a beneficial effect.”
An Alzheimer's drug that would provide quick cognitive benefits and progressive disease modification would have enormous impact, according to Dr. Peter Whitehouse. But disappointment over past efforts to enhance the cholinergic system, including today's cholinesterase inhibitors, has provoked concern about this new pharmacotherapy.
“Maybe if the cholinesterase inhibitors had worked better, we'd be seeing a different climate for NRAs,” said Dr. Whitehouse, professor of neurology at Case Western Reserve University, Cleveland. “It will be a challenge to find drugs with an effect size much larger than current cholinesterase inhibitors.”