Nicotinic receptor loss has been implicated in the pathogenesis of Alzheimer's disease. The present study investigated the effects of chronic low-dose transdermal nicotine in a cohort of nondemented, healthy volunteers (mean age 63 years). The majority of subjects (85%) had a first-degree relation with dementia. Subjects were tested using a before, during, and after design on a battery of tests known to be sensitive to early cognitive decline. A mixed pattern of results was seen, with significant changes occurring with verbal learning, object learning, delayed recall, and word retrieval. Nicotine had no effect on measures of concentration or psychomotor speed. The effects were most noticeable in subjects at the lower end of baseline test performance on the tasks used. The results are discussed with reference to the relationship between strategic nicotinic receptor loss and measurable psychometric change. The potential therapeutic role of nicotinic agonists in preclinical “at risk” individuals is supported by the results of this study.