This trial aims to test whether one year of Varenicline, when compared to placebo, can reduce fall risk and show improvement in the ability to multitask while walking.

Participants that are eligible after screening for the study will be randomized to receive Varenicline or placebo. Along with the study medication participants will have visits (over the phone and in person), various tests and imaging, questionnaires, and laboratory collections.

The hypothesis of the trial are:

• The primary hypothesis is that varenicline will result in less progress in dual-task cost gait performance after 12 months of treatment compared to placebo in hypocholinergic Parkinson disease (PD) Mild Cognitive Impairment (MCI) patients.
• The primary secondary hypothesis assesses whether the magnitude of effect of varenicline relative to placebo is consistent with the minimal clinically important difference (MCID) for the relative risk of falls in the 12-month double-blind treatment period.

Inclusion Criteria:

• Participants with a PD diagnosis based on the Movement Disorders Society Clinical Diagnostic Criteria for Parkinson's Disease at the time of baseline screening/enrollment visit
• Participants with occipital association cortex cholinergic denervation in the lowest tertile of the normal range on F-fluoroethoxybenzovesamicol (FEOBV) Positron Emission Tomography (PET)
• Participants with legally authorized representatives (LARs) able to co-sign documented informed consent or participants that have capacity to provide informed consent upon study enrollment as ascertained by the study-specific University of California, San Diego Brief Assessment of Capacity to Consent (UBACC)
• Mild Cognitive Impairment consistent with Parkinson disease Mild Cognitive Impairment (PD-MCI)

Exclusion Criteria:

• Atypical Parkinsonian conditions other than Parkinson disease (PD)
• Participants initially on certain dopamine blocking drugs (per protocol), specific anticholinergic drugs (trihexyphenidyl, benztropine), or specific cholinesterase inhibitor drugs (per protocol) at the in-person screening visit
• Modified Hoehn and Yahr score of 4.0 or greater at the in-person screening visit
• Current or previous (within last 6 months of in-person screening visit) use of any product or medication containing nicotinic agents, including use of tobacco products such as cigarettes, cigars, pipes, chewing tobacco, etc., e-cigarettes, over the counter (OTC) nicotine patches, chewing gum containing nicotine, or varenicline
• Evidence of a stroke with both cortical and subcortical involvement or occipital lobe mass lesion on structural magnetic brain imaging (MRI) obtained at the in-person screening visit that would preclude co-registration and analysis of FEOBV PET data
• Participants where magnetic resonance imaging (MRI) is contraindicated including, but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, or cochlear implant
• Severe claustrophobia precluding MRI or PET imaging
• Participants limited by participation in research procedures involving ionizing radiation
• Pregnancy (test within 48 hours of the PET imaging session in women of childbearing potential) or breastfeeding at the time of in-person screening visit
• Participants with stage 4 or 5 chronic kidney disease at the time of in-person screening visit (estimated Creatinine Clearance < 30 milliliters per minute)
• Current, significant mood disorder at the time of in-person screening/enrollment visit defined as follows: persistent (lasting longer than 2 weeks) symptoms of depression or anxiety in the 30 days preceding informed consent, as determined by self-report
• Evidence of active suicidal ideation as defined by an affirmative answer to either question 1 or 2 on the Columbia Suicide Severity Rating Scale (C-SSRS)
• History of a myocardial infarction or unstable angina in the 90 days preceding enrollment visit
• A current or previous history of epilepsy or any epileptic seizures in the 12 months preceding enrollment
• Heavy alcohol use as defined by a score of 8 or greater on the Alcohol Use Disorders Identification Test (AUDIT-self-report version) at the time of screening/enrollment visit
• Participants that are unable to swallow pills
• Participants with a history of allergic reaction to varenicline
• Participants that are actively taking part in another ongoing interventional (i.e., not observational) clinical trial

The study team will ensure the dataset is shared by the occurrence of the earlier of the following two milestones: either the date of primary publication or within 9 months of lifting of the data lock.

De-identified subject data will be uploaded in a timely manner to a data repository using an established data transfer mechanism and the NINDS supported Common Data Elements (CDEs) as appropriate. Pending appropriate permissions, biospecimens (DNA) will be banked in the NINDS biorepository. Uploaded datasets will be coded and stripped of identifiers in order to prevent the possibility of identifying participants in this study from the publicly available dataset.

Access to the dataset that is uploaded to the data repository is available to any individual that applies to them for data access. This process does not place any limitations on the use of the data for commercial purposes.

This is a double-blind study. The study personnel (except for select staff at the Data Coordinating Center (DCC) and research pharmacy).