OBJECTIVE: To learn if acetylcholinesterase inhibitors alter verbal recall by improving semantic encoding in a double-blind randomized placebo-controlled trial. BACKGROUND: Cholinergic supplementation has been shown to improve delayed recall in adults with Alzheimer disease. With functional magnetic resonance imaging, elderly adults, when compared with younger participants, have reduced cortical activation with semantic processing. There have been no studies investigating the effects of cholinergic supplementation on semantic encoding in healthy elderly adults. METHOD: Twenty elderly participants (mean age 71.5, SD±5.2) were recruited. All underwent memory testing before and after receiving donepezil (5 mg, n=11 or 10 mg, n=1) or placebo (n=8) for 6 weeks. Memory was tested using a Levels of Processing task, where a series of words are presented serially. Subjects were either asked to count consonants in a word (superficially process) or decide if the word was "pleasant" or "unpleasant" (semantically process). RESULTS: After 6 weeks of donepezil or placebo treatment, immediate and delayed recall of superficially and semantically processed words was compared with baseline performance. Immediate and delayed recall of superficially processed words did not show significant changes in either treatment group. With semantic processing, both immediate and delayed recall performance improved in the donepezil group. CONCLUSIONS: Our results suggest that when using semantic encoding, older normal subjects may be aided by anticholinesterase treatment. However, this treatment does not improve recall of superficially encoded words. © 2008 by Lippincott Williams & Wilkins.