A major thrust of clinical research in cognition and aging has been directed towards the identification and potential treatment of the pre-Alzheimer condition known as Mild Cognitive Impairment (MCI). Patients with amnestic MCI appeared to have a high risk of developing dementia, with 12- 15% per year progressing to the point where they meet criteria for Alzheimer's disease, and 50-60% being diagnosed with dementia within five years. Developing effective treatments that will improve symptoms of memory loss and delay or retard the development of dementia in patients who are at high risk is an extremely important public health goal. A number of treatment approaches are being considered or tested including acetylcholinesterase inhibitors, high dose vitamins, hormones, etc. Alterations in brain systems that involve CNS nicotinic receptors appear to be critically important in the development of cognitive impairment resulting in dementia. Loss of nicotinic receptors is one of the most reliable receptor-based findings in Alzheimer's disease and this loss correlates with cognitive impairment. Blockade of nicotinic receptors in normals leads to reversible cognitive impairment in the same domains that are affected in MCI and Alzheimer's disease. Stimulation of nicotinic receptors with nicotine or and/or novel nicotinic agonists reliably improves certain aspects of attentional and memory functioning in both normal individuals, patients with ADHD, schizophrenia, patients with Alzheimer's disease, and in our preliminary studies, MCI patients. Nicotine is arguably the most well studied cognition-enhancing substance known, with hundreds of studies in both tobacco and non-tobacco forms. Furthermore, nicotinic stimulation appears to have significant neuroprotective effects and nicotinic stimulation may have positive influences on APP processing. We propose a pilot 6 month double-blind placebo-controlled trial of transdermal nicotine in 60 patients with amnestic MCI with a 6-month open label extension. Our primary goal is to demonstrate that transdermal nicotine is safe to administer to the non-smoking MCI patients over a one year period. Our secondary goal is to demonstrate cognitive symptom relief/improvement and to gain some preliminary data regarding prevention of progression. Transdermal nicotine has proved to be a extremely safe method of administering nicotine that eliminates the liabilities of tobacco associated nicotine. Patients will be recruited, screened, and treated at 3 major medical centers by investigators who have been leaders in clinical and basic science nicotinic research. Subjects will be tested utilizing sophisticated computerized and non-computerized methodology. Close clinical follow-up will insure patient safety. For reasons outlined above, transdermal nicotine may be an excellent way of improving cognitive performance and delaying progression of MCI. If nicotine proves successful in alleviating cognitive symptoms and in improving global outcomes along with reasonable safety, we will propose a large multicenter clinical trial.
