Falls are a major problem for people with Parkinson disease (PD). Falls and their sequelae are the leading cause of hospitalizations, precipitate institutionalization, and increase mortality in PD. No available therapy markedly mitigates fall risk and fall reduction is a major unmet therapeutic need in PD. A considerable body of clinical and preclinical research links fall risk, impaired cognition, particularly impaired attentional function, and brain cholinergic deficits in PD. Approximately two thirds of people with PD at a moderate stage have cortical cholinergic deficits detectable in vivo with [18F]FEOBV positron emission tomography (PET). In broad terms, cholinergic projection system impairments correlate with mild cognitive features in PD and gait impairments, but cholinergic therapeutic development has been hampered to date by the non-specific effects of currently available cholinesterase inhibitors and clinical trial designs that failed to target biologically and functionally relevant outcomes in participants at greatest risk. Preclinical research suggests that stimulation of α4β2 nicotinic cholinergic receptors would enhance attention and diminish fall risk. We performed a successful target engagement study of the α4β2 nicotinic agonist varenicline (VCN; Chantix) in PET confirmed hypo cholinergic PD participants. VCN treatment was well tolerated, had high α4β2 receptor occupancy, and produced relevant physiologic effects on gait and attention including reduced dual tasking cost during normal pace (npDTC) walking. We propose a single-site phase II trial in PD participants with Mild Cognitive Impairment (PD-MCI) to address a rigorous go/no-go rule determining if a multi-center large scale efficacy trial is justified. PD-MCI participants will be screened with [18F]FEOBV PET at the time of enrollment and only hypo cholinergic subjects will be randomized. In a double-masked, parallel-group trial of VCN vs placebo in PD-MCI participants, our primary endpoint will be the durability of VCN’s effect on relevant gait-attentional dual tasking performance. An important secondary endpoint will be 1 year fall reduction in the range of the Minimal Clinically Important Difference (MCID). We will explore the effect of the randomized varenicline intervention on a novel hierarchical composite endpoint of fall-related injuries, falls, and near-falls over 12 months as a future potential endpoint for fall intervention trials in PD. If our hypotheses are verified, we will have critical evidence to justify a multicenter phase III efficacy trial of VCN for fall risk mitigation in PD. Even with a negative outcome, we will introduce and test novel methods for future clinical trials aimed at fall risk mitigation in PD.