This study will ascertain whether nicotine is safe and tolerable in DS patients, help with dose-ranging of nicotine in DS, look for evidence of enhancements in cognitive functioning, and establish evidence for biological and behavioral correlates of nicotinic stimulation effects. The knowledge gained from the translational aspects of this project may also guide the application of new nicotinic drugs in DS and generate, for the first time, data on the importance of nicotinic receptor changes in the development of cognitive impairment in DS adults.

Hypotheses:

• Transdermal nicotine treatment will be well tolerated out to one month by non-smoking DS patients without significant adverse effects.
• Nicotine will enhance cognitive performance by one month compared to baseline and post-treatment testing.
• Nicotine will enhance functioning detectable by clinician and/or informant ratings (pre-post).

Over 50% of adults with Down Syndrome (DS) develop Alzheimer's disease (AD) by the age of 60 (Nadel 2003), and life expectancy in DS is now 50-60 years. Thus, age-associated cognitive impairment and dementia in older adults with DS is an urgent public health concern. The investigators propose that nicotinic stimulation is a promising strategy to stabilize or improve cognitive functioning in adults with DS, possibly with additional neuroprotective effects. The investigators have extensive experience investigating the role of nicotinic receptors on human cognition and impairment. This application takes advantage of new insights into treating Mild Cognitive Impairment (MCI-the precursor condition to Alzheimer's Disease (AD) in typically developing individuals) with nicotine to propose an open label pilot study of transdermal nicotine in middle-aged non-smoking DS patients who show early cognitive and/or behavioral changes consistent with MCI/dementia.

The goal of this study is to establish preliminary evidence for safety, gain preliminary evidence as to whether nicotine enhances cognitive functioning in DS adults, and examine electrophysiological, biological, and behavioral correlates of nicotinic stimulation effects.

The investigators propose that positive results on cognitive or functional indices that would lead to a larger and longer double-blind trial to test more definitively whether nicotinic stimulation may be cognitively and/or functionally enhancing for DS patients. The knowledge gained from the translational aspects of this project will guide the development of potentially new nicotinic drugs in DS and generate, for the first time, data on the importance of nicotinic receptor changes in the development of cognitive impairment in DS adults. This work also represents the first time that cutting-edge advances in treating MCI/AD in the general population are immediately and rigorously applied to those with DS.

Inclusion Criteria:

• Cognitive complaints and/or memory difficulties which are verified as new onset by an informant.
• Cognitive Global Rating consistent with mild impairment or deterioration from premorbid baseline.
• General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease/dementia cannot be made by the physician at the time of the screening visit.
• No significant cerebrovascular disease: Modified Hachinski score of less than or equal to 4.
• Age 25+.
• Stable medications for at least 1 month prior to screening. Central nervous system (CNS) medications should be stable for 3 months.
• No evidence of major depression.
• Informant is available who has frequent contact with the subject (e.g. an average of 10 hours per week or more).
• Adequate visual and auditory acuity to allow neuropsychological testing.
• Good general health with no additional diseases expected to interfere with the study.
• Normal B12, rapid plasma reagin (RPR), and Thyroid Function Tests or without any clinically significant abnormalities that would be expected to interfere with the study.
• ECG without clinically significant abnormalities that would be expected to interfere with the study.
• Subject is not pregnant, lactating.
• Subjects will be taking no drugs with cholinergic properties (e.g donepezil).
• Agreement not to take other vitamin or supplements other than multivitamins.
• Negative urine pregnancy test in females.

Exclusion Criteria:

• Any significant neurologic disease such as Alzheimer's disease, Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities.
• Active Major depression or another major psychiatric disorder as described in DSM-IV.
• History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).
• Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol including:
• History of myocardial infarction in the past year or unstable or severe cardiovascular disease including angina or congestive heart failure (CHF) with symptoms at rest.
• Clinically significant obstructive pulmonary disease or asthma.
• Clinically significant and unstable gastrointestinal disorder such as ulcer disease or a history of active or occult gastrointestinal bleeding within two years.
• Clinically significant laboratory test abnormalities on the battery of screening tests (hematology, chemistry, urinalysis, ECG).
• Insulin-requiring diabetes or uncontrolled diabetes mellitus.
• Uncontrolled hypertension (systolic BP> 170 or diastolic BP> 100).
• Use of any investigational drugs within 30 days or 5 half-lives, whichever is longer, prior to screening.

6-weeks

Adverse events collected through query of subjects about any new or worsening problems or side effects, conducted at each contact.