Precursor conditions to Alzheimer’s disease (AD) such as Mild Cognitive Impairment (MCI) are now a target of patient identification and potential treatment, as studies clearly showing that the risk of progression to dementia is very high. Despite attempts to develop new treatments for AD and its precursor, MCI, methods of interrupting the course of illness and preventing progression have proven elusive. Treatment strategies for AD or MCI based on molecular pathologies (such as Aβ) have thus far produced equivocal or negative results. Losses of cholinergic neurons and particularly nicotinic cholinergic receptors have been shown to be principally related to cognitive decline in AD. However, currently approved treatments for AD have not significantly improved MCI, despite clear evidence of alteration of cholinergic function at this stage, Thus nonspecific enhancement of cholinergic function does not appear to be a fruitful strategy for either enhancing long-term cognitive functioning in MCI, nor retarding the progression to AD. There is a continuing search for new treatments that will improve cognitive symptoms while potentially be disease modifying. Nicotine may be one of those molecules and is easily available, inexpensive, and easy to use. We have previously performed a double-blind 6-month pilot trial showing that nicotine treatment significantly improved cognitive performance in the areas of attention and episodic memory, showed improving global ratings of functioning and self-rated memory problems, and was well tolerated with an impressive safety profile and no abuse liability. In the previous grant period, we initiated a larger longer trial, a definitive 2-year multi-center clinical trial to test whether daily transdermal nicotine will produce sustained cognitive, clinical, and functional benefits in patients with MCI and to test whether nicotine will change the underlying biology related to developing AD by monitoring biological markers including structural and functional brain imaging and measures of AD pathology in spinal fluid. In this subsequent grant period, we will enlarge the cohort to account for COVD-19 pandemic attrition, complete the enrollment of the study, and take advantage of new biomarker approaches (e.g. amyloid PET) to expand our analysis of the potential impact of nicotine on brain pathology of MCI/AD. This proposed study has broad clinical and scientific significance. If the hypotheses are validated, these findings would support a novel, broadly available, and inexpensive intervention for MCI. Further, the unique biological information will be obtained regarding the effects of nicotinic stimulation on AD biomarkers, brain structure/function, and brain amyloid will make an invaluable contribution to AD research. This will be the longest trial of nicotinic stimulation on brain function to date and if successful would lead to combined trials with other symptomatic agents and/or agents that directly interact with Aβ or tau...