This 7-year randomized controlled trial will compare the efficacy of non-invasive brain stimulation (trans-cranial Direct Current Stimulation - tDCS) combined with cognitive remediation (CR) versus sham ("placebo") tDCS combined with sham ("placebo") CR in slowing down cognitive decline and preventing Alzheimer's Dementia in older persons with mild cognitive impairment or major depressive disorder with or without mild cognitive impairment.

By the time Alzheimer's Dementia (AD) and related disorders (ADRD) are diagnosed the brain has sustained substantial insult that limits the efficacy of current treatments. Preventive interventions are urgently needed but prevention studies require large numbers of participants and long follow-up periods unless they can target a high-risk population.

The investigators propose to study the efficacy of a preventive intervention for AD in three high risk groups: (1) older persons with Mild Cognitive Impairment (MCI); (2) older persons with a major depressive disorder (MDD) without MCI; and (3) older persons with MDD and MCI.

MCI is considered a prodromal condition for dementia with a progression rate of about 1% per month. MDD has independently been identified as one of the most promising targets for AD prevention studies since, even after successful treatment of their depressive episode, older persons with remitted MDD develop MCI or dementia at a rate of 1-2% per month.

The investigators proposed intervention is a combination of cognitive remediation (CR) and non-invasive brain stimulation - transcranial Direct Current Stimulation (tDCS). Participants with MCI or MDD (with or without MCI) will be randomized to tDCS + CR or sham ("palcebo") tDCS + sham ("placebo") CR. Both CR and tDCS have been shown to induce neuroplasticity and improve cognition. The investigators hypothesize that their combination will enhance cognitive reserve and protect against cognitive decline and the onset of MCI in those with "normal" cognition or AD in those with MCI.

The investigators design is informed by their experience conducting randomized controlled trials (RCTs) in older participants with dementia, MCI, or MDD over more than two decades. In the investigators recent donepezil prevention trial, combining donepezil with standard antidepressant maintenance prevented cognitive decline and the incidence of dementia in participants who had had both MDD and MCI. Building on this prevention trial, the investigators conceptualize the proposed study as a high-risk, high-gain RCT aimed at enhancing cognitive reserve and preventing cognitive decline and dementia in a high risk population. If the investigators are successful in this high risk population, then tDCS + CR can be tested in, and extended to, the general population (i.e., for universal prevention) or other groups at high risk for AD (i.e., for selective or indicated prevention).

Five Toronto academic sites with a history of successful collaboration will consent up to a total of 500 participants meeting criteria for MCI (age 60 and older) or MDD (age 65 and older) to reach a target of 375 enrolled participants initiating the study intervention. Participants will be randomized to either: i) tDCS + CR or ii) sham tDCS + sham CR. They will first receive tDCS + CR (or sham + sham) 5 days a week for 8 weeks, followed by home-based CR (or sham) and booster sessions of tDCS + CR (or sham + sham) for 5 days every 6 months until they develop dementia (or MCI for those who are deemed cognitively intact at baseline) or complete the study.

During the COVID-19 pandemic, the study has been modified to be administered in a hybrid manner to accommodate both in-person and virtual assessments. Clinical and cognitive assessments (every 12 months) can be done in person or remotely (via telephone or using WebEx/Zoom). Some assessments are modified to accommodate the change in format of administration while maintaining the validity and integrity of the data. The assessments that cannot be done via phone or videoconference will temporarily not be done.

Similarly, the intervention booster group sessions (every 6 months) can also be provided in two formats of in-person or virtual (via WebEx or Zoom) sessions. The tDCS administration cannot be done remotely and hence the virtual booster sessions will only consist of the CR exercises.

MCI Group

Inclusion:

• Age > 60 (on day of randomization)
• DSM 5 criteria for Mild Neurocognitive Disorder ("MCI")
• Willingness to provide informed consent
• MADRS score of 10 or below
• Availability of a study partner who has regular contact with the participant
• Ability to read and communicate in English (with corrected vision and hearing, if needed)

Exclusion:

• Met DSM 5 criteria for Major Depressive Episode in past 10 years
• Lifetime DSM 5 diagnosis of schizophrenia, bipolar disorder, or OCD
• DSM 5 diagnosis of alcohol or other substances use disorder within the past 12 months
• High risk for suicide
• Significant neurological condition (e.g., stroke, seizure disorder, MS)
• Unstable medical illness, (e.g., uncontrolled diabetes mellitus or hypertension)
• Having taken a cognitive enhancer (acetylcholinesterase inhibitor or memantine) within the past 6 weeks.
• Participants taking anticonvulsants, and other psychotropic medication (see exceptions below) that cannot be safely tapered and discontinued. The following psychotropic medications are allowed: i) any antidepressant; ii) zopiclone, trazadone, or a benzodiazepine if they have been taken at a stable dose for at least 4 weeks prior to study entry and; iii) gabapentin and pregabalin if they have been taken at a stable dose for at least 4 weeks prior to study entry AND if prescribed for chronic pain.
• A pace-maker or other metal implants that would preclude safe use of tDCS.

MDD Group

Inclusion:

• Age ≥ 65 (on day of randomization)

• Meets DSM 5 criteria for one or more MDE(s)with:

  1. an offset of 2 months to 5 years from the screening visit date. It is not necessary for this (these) episode(s) to have received medical attention OR
  2. an offset of 5 years or more from the screening visit date. It is necessary that at least one MDE received medical attention (e.g., previously been on one or more antidepressant(s), saw a psychiatrist, primary care physician, or had a previous hospitalization). Also, the MDE must have occurred during the participant's adult life (i.e., at 18 years of age or older).

• MADRS score of 10 or below

• Willingness to provide informed consent

• Availability of a study partner who has regular contact with the participant

• Ability to read and communicate in English (with corrected vision and hearing, if needed)

Exclusion:

• Meets DSM 5 criteria for Major Neurocognitive Disorder ("dementia")
• Lifetime DSM 5 diagnosis of schizophrenia, bipolar disorder, or OCD
• DSM 5 diagnosis of alcohol or other substances use disorder within the past 12 months.
• High risk for suicide.
• Significant neurological condition (e.g., stroke, seizure disorder, MS)
• Unstable medical illness (e.g., uncontrolled diabetes mellitus or hypertension)
• Participants taking anticonvulsants, and other psychotropic medication (see exception below) that cannot be safely tapered and discontinued. In addition to any antidepressant, the following psychotropic medications are allowed if they have been taken at a stable dose for at least 4 weeks prior to study entry: zopiclone, trazodone, or a benzodiazepine; and gabapentin or pregabalin if prescribed for chronic pain.
• Having taken a cognitive enhancer (acetylcholinesterase inhibitor or memantine) within the past 6 weeks.
• A pace-maker or other metal implants that would preclude safe use of tDCS.
• Received electroconvulsive therapy (ECT) within 6 months of baseline neruopsychological testing.

Control group

Inclusion:

• Age > 60
• MADRS score of 10 or below
• Willingness to provide informed consent
• Ability to read and communicate in English (with corrected vision and hearing, if needed)

Exclusion:

• Meets DSM 5 criteria for Minor or Major Neurocognitive Disorder
• Any other lifetime DSM 5 diagnosis except for simple/specific phobias
• Significant neurological condition (e.g., stroke, seizure disorder, MS)
• Unstable medical illness, (e.g., uncontrolled diabetes mellitus or hypertension)
• Participants taking anticonvulsants, and other psychotropic medication (see exception below) that cannot be safely tapered and discontinued. The following psychotropic medications are allowed if they have been taken at a stable dose for at least 4 weeks: zopiclone up to 15 mg/day; trazadone up to 150 mg/day; benzodiazepine at a dose of up to 3 mg/day lorazepam-equivalents; gabapentin and pregabalin (if prescribed for pain).
• A pace-maker or other metal implants
• Neuropsychological testing within the past 12 months