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December 15, 1999

Cholinergic Markers in Alzheimer Disease—Reply

Author Affiliations

Phil B.FontanarosaMD, Interim CoeditorIndividualAuthorMargaret A.WinkerMD, Deputy EditorIndividualAuthorStephenLurieMD PhD, Fishbein FellowIndividualAuthor

JAMA. 1999;282(23):2208-2209. doi:10-1001/pubs.JAMA-ISSN-0098-7484-282-23-jbk1215

In Reply: Drs Bartus and Emerich state, "In fact, ChAT can be inhibited up to 90% with no measurable effects on acetylcholine synthesis or release." One can extrapolate from this point that the smaller reductions in ChAT and AChE activity that were observed in the early and mildly impaired patients with AD whom we studied would be unlikely to produce a deficit in cholinergic neurotransmission.

Bartus and Emerich also point to the plethora of experiments in animal model systems (some of which have been contributed by our group), showing that deficits in forebrain cholinergic systems can result in significant learning and memory deficits. Although some studies have questioned the validity of these findings,1,2 we agree that manipulations that adversely affect the forebrain cholinergic system can impair learning, memory, and cognition. However, this fact cannot be interpreted to mean that all cognitive deficits result from forebrain cholinergic system dysfunction. It is quite possible that the dysfunction in early AD has its origin in something other than the cholinergic system. The contention that it is possible that cholinergic system deficits occur in AD "well in advance of the death of cholinergic neurons" is a hypothesis that must be tested. That such a state in animal model systems can produce cognitive deficits does not obligate it to occur in AD, and the results of our studies, although not definitive in this regard, cast doubt about this contention.

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