Investigators are doing this research study to find out if methylphenidate (MPH) can help people with Mild Cognitive Impairment (MCI) or mild dementia likely due to Alzheimer's Disease (AD) and related disorders (ADRD).

The study drug MPH is approved by the U.S. Food and Drug Administration (FDA) to treat Attention Deficit/Hyperactivity Disorder (ADHD), but MPH is not approved by the FDA to treat Mild Cognitive Impairment or mild dementia related to Alzheimer's Disease. However, other studies have been done in which MPH has been given to people with neurodegenerative dementias and results have shown some improvement in these people's mood and cognition. Investigators would like to see if MPH will help mood and cognition.

This study will take place completely virtually (with the option to come in for the first visit to meet the study team). All study visits will occur over a secure videoconferencing platform. All study materials will be shipped directly to the home of each participant.

Investigators will give participants a supply of study drug. Participants will take the study drug by mouth once a day for 16 weeks. It is important for participants to follow our instructions about how to take the study drug. Participants can take the drug with or without food. Investigators will provide enough study drug for participants to take until the next visit.

For this study, there are 3 blocks: each month-long block will consist of MPH for a two-week period (I.e. "A" Blocks 1, 2, 3) and PBO for a two-week period (I.e. "B" Blocks 1, 2, 3) in random assignment order for each block. Thus, all volunteers will receive a four-week PBO-lead in and acclimatization followed by treatment with MPH or matching PBO for eight-weeks each in three randomized sequence crossover blocks for a total of 10 weeks of PBO and 6 weeks of MPH.

Weekly Tasks During the study, certain tasks must be done each week.

Every Day:

The following tasks must be done each day throughout the study:

• Wear the activity tracker
• Take study medication

Six Days per Week:

The following tasks will be completed six days per week:

• Complete online cognitive games

  o Use online brain games to rate daily mood and sleep quality

• Synchronize Fitness tracker to study provided tablet (if requested)

Once every five days:

The following activities must be done approximately every five days throughout the trial:

• Charge Fitness tracker during a time when the subject is resting but not sleeping

The study coordinator will periodically log into both the Fitness tracker dashboard and the online brain game account to check the battery level of the Fitness tracker, ensure the Fitness tracker is synching to the Fitness tracker dashboard, and monitor the completion of cognitive exercises.

Inclusion Criteria:

• Study subjects meeting all of the following criteria will be allowed to enroll in the study:

  1. Aged 55-95 inclusive;
  2. Diagnosis of MCI or mild-stage dementia presumed due to AD and AD-related disorders;
  3. Cognitive abilities sufficient to be able to complete all study tasks as determined by the PI or a Co-I;
  4. Education level, English language skills, and literacy that indicates participant will be able to comprehend all assessments;
  5. Neuropsychiatric Inventory Agitation/Aggression Question 4 = "No" or "Yes" with a mild severity rating.
  6. Willing and able to complete all assessments and study procedures;
  7. Not pregnant, lactating, or of child-bearing potential
  8. Volunteer has a Study Partner with at least two days per week of contact and willing to complete partner study forms;
  9. No exclusionary medications or dietary supplements. See Section 6.5.8.1
  10. If on cholinesterase inhibitor and/or memantine, doses are stable for 3 months prior to baseline.
  11. Basic video conferencing capabilities and a willingness to participate in a virtual trial (including self-administration of ECG).

Exclusion Criteria:

• Subjects meeting any of the following criteria during the screening evaluation will be excluded:

  1. Any history of specific CNS disease other than AD or AD-related disorders, such as major clinical stroke, brain tumor, normal pressure hydrocephalus, multiple sclerosis, significant head trauma with persistent neurological or cognitive deficits or complaints;
  2. Clinically significant or unstable medical condition that could affect safety or compliance with the study and would, in the opinion of the investigator, pose a risk to the participant if they were to participate in the study;
  3. Major active or chronic psychiatric illness (e.g. depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) within the previous year;
  4. Current suicidal ideation or history of suicide attempt;
  5. History of alcohol or other substance abuse or dependence with the past two years;
  6. Clinically significant abnormalities on complete blood count, comprehensive metabolic panel, B12, or TSH screening safety lab results;
  7. Concomitant use of medications with psychoactive properties that may deleteriously affect cognition (anticholinergics, antihistamines, antipsychotics, sedative hypnotics, anxiolytics);
  8. Treatment with monoamine oxidase inhibitors, coumadin, phenobarbital, phenytoin, primidone, tricyclic antidepressants or other medicines with potential for clinically significant interaction;
  9. Hypersensitivity to MPH;
  10. History of marked anxiety and agitation, ADHD, motor tics, glaucoma, or a history or family history of Tourette's Syndrome;
  11. Clinically significant cardiac condition for which MPH may be contradicted as determined by study physician, such as MI or ventricular arrhythmia within 6 months of enrollment;
  12. History of untreated, uncontrolled hypertension or a blood pressure greater than 150/90 during the screening period;
  13. Use of other small molecule or device- based investigational agents one month prior to entry and for the duration of the trial.

Participants were analyzed in treatment/placebo groups based on randomized crossover assignment.

Adverse event data was collected from each participant up to 18 weeks