The purpose of the study is to see if daily transdermal nicotine is able to produce a significant cognitive, clinical and functional improvement in participants with MCI. Neuronal nicotinic receptors have long been known to play a critical role in memory function in preclinical studies, with nicotine improving attention, learning, and memory function.

The study will enroll 380 participants for a 2 year period. Participants will be randomized (50:50) to either the transdermal nicotine, beginning at 7mg/day, and increasing to 21mg/day, or placebo skin patch.

Inclusion Criteria:

1. Participant must have a subjective memory concern as reported by participant, study partner, or clinician

2. Abnormal memory function documented by scoring within the education adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale - Revised:

   • less than or equal to 11 for 16 or more years of education
   • less than or equal to 9 for 8 - 15 years of education
   • less than or equal to 6 for 0 - 7 years of education

3. Mini-Mental State Exam score between 24 and 30, inclusive

4. Clinical Dementia Rating (CDR) Global = 0.5. Memory Box score must be at least 0.5

5. General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease dementia cannot be made by the site physician at the time of the screening visit

6. Age 55-90 (inclusive)

7. Stable permitted medications for 4 weeks or longer as specified in Section 6, including:

   • Memantine and cholinesterase inhibitors are allowable if stable for 12 weeks prior to screen

8. Geriatric Depression Scale score of less than or equal to 14

9. Study Partner is available who has frequent contact with the participant (e.g. an average of 10 hours per week or more), and can accompany the participant to most visits to answer questions about the participant

10. Adequate visual and auditory acuity to allow neuropsychological testing

11. Good general health with no additional diseases/disorders expected to interfere with the study

12. Participant is not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile)

13. Completed six grades of education or has a good work history

14. Fluent in English or Spanish

Exclusion Criteria:

1. Regular use of tobacco products within the past year, such as smoking (cigarettes, pipes, cigars, etc.) or use of other nicotine products (chewing tobacco, e-cigarettes, nicotine patches, gum, sprays, etc.).

2. Any significant neurologic disease such as Alzheimer's disease dementia, 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.

3. Major depression, bipolar disorder as described in DSM-V within the past 1 year or psychotic features, agitation or behavioral problems within 3 months, which could lead to difficulty complying with the protocol

4. History of schizophrenia (DSM V criteria)

5. History of alcohol or substance abuse or dependence within the past 2 years (DSM V criteria)

6. Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic disease in the opinion of the Investigator, may either put the participant at risk because of participation in the study, or influence the results, or the participant's ability to participate in the study.

7. Has had a history within the last 5 years of a primary or recurrent malignant disease with the exception of non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen post-treatment

8. Clinically significant abnormalities in B12 or TFTs (Thyroid Function Tests) that might interfere with the study. A low B12 is exclusionary, unless the required follow-up labs (homocysteine (HC) and methylmalonic acid (MMA)) indicate that it is not physiologically significant.

9. Clinically significant abnormalities in screening laboratories or ECG.

10. Residence in skilled nursing facility.

11. Use of any excluded medication as described in the protocol, including:

    • Use of centrally acting anti-cholinergic drugs
    • Use of any investigational drugs within 30 days or 5 half-lives, whichever is longer, prior to screening.

12. For CSF sub-study participants, a current blood clotting or bleeding disorder, or significantly abnormal PT or PTT (partial thromboplastin time) at screening

13. For MRI sub-study participants, contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker.

14. Patients whom the Site PI deems to be otherwise ineligible.