Cognitive Training and Neuroplasticity in Mild Cognitive Impairment: COGIT-2 Trial

Inclusion Criteria: 1. Access to a home desktop or laptop computer or tablet at acceptable internet speed for the study duration. 2. Participants need to be 55 to 89 years of age (inclusive) at the time of informed consent. 3. Females need to be post-menopausal (last period more than 12 months earlier by history). 4. Subjective cognitive complaints, i.e., memory or other cognitive complaints, e.g., naming/language. 5. Meets criteria for cognitive impairment (CI), including either EMCI (early MCI) or LMCI (late MCI), defined as memory impairment documented by scoring below the education adjusted cutoff on the Logical Memory II subscale (Story A, Delayed Paragraph Recall) from the Wechsler Memory Scale - III (WMS-III) (the maximum score is 25). The criteria for MCI (includes EMCI and LMCI) and used in COGIT-2 are as follows: EMCI is defined by a WMS-III Logical memory delayed recall score of 3-6 with 0-7 years of education, score of 5-9 with 8-15 years of education, and score of 9-11 with 16 or more years of education. LMCI is defined by a WMS-III Logical Memory delayed recall score ≤ 2 with 0-7 years of education, score ≤ 4 with 8-15 years of education, and score ≤ 8 with ≥ 16 years of education. 6. Montreal Cognitive Assessment (MoCA) score ≥ 20/30. 7. An informant (relative, friend, other caregiver) who contacts the participant at least weekly is required to provide information about the participant's functioning. This can be a telephone informant in the case of participants who do not have a live-in informant or close significant other. If the informant drops out, an alternate informant can be designated by the participant but the new informant will need to sign the informant information sheet in person. 8. Must be English-speaking: Wide Range Achievement Test (WRAT3) score must indicate at least a 6th grade reading level with a score of ≥ 37. Exclusion Criteria: 1. Diagnosis of dementia of any type. 2. Current clinical diagnosis of schizophrenia, schizoaffective disorder, psychosis, or bipolar I disorder (Diagnostic and Statistical Manual of Mental Disorders (DSM-5 TR) criteria). 3. Current unstable or untreated major depression, or active suicidality based on a Suicide Severity Rating Scale (C-SSRS Screen version: positive answer to question 1 or 2 followed by item 6 positive answer leads to exclusion. Negative answer to questions 1 and 2: interview ends and the participant is not excluded for active suicidality). 4. Current or recent (past 6 months) alcohol or substance use disorder (DSM-5 TR criteria). 5. Clinical stroke with residual neurological deficits. While we will not exclude participants with cerebrovascular disease or transient ischemic attacks (TIAs), we do not wish to include participants with a frank clinical stroke because it is not clear that this type of participant is similar to the MCI participant generally, and clear-cut neurological impairment, e.g., hemiplegia/hemiparesis or speech impairment, may compromise the ability to do the procedures and to complete the neuropsychological test battery. 6. Use of medications known to have a negative impact on cognition: benzodiazepines in lorazepam equivalents greater than or equal to 1 mg daily, narcotics, anticholinergics (ACB Calculator level 3 medication leads to exclusion), large number of sedating medications in combination. Medications with anticholinergic/antihistaminergic properties will be reviewed, e.g., low dose quetiapine (≤ 25 mg daily) will be permitted, but daily use of diphenhydramine or equivalent will be reviewed. Current use of lecanemab or donanemab will be exclusionary. 7. Presence of any of the following disorders: a) Central Nervous System Infections, with cerebrospinal fluid evidence of meningitis, encephalitis, or other infectious process; b) dementia of any type; c) Huntington's disease; d) Multiple sclerosis; e) Parkinson's disease; f) Other neurologic disorders with focal signs, e.g., amyotrophic lateral sclerosis. 8. Acute, severe unstable medical illness in the judgment of the clinician. For cancer, acutely ill participants (including those with metastases) are excluded, but history of successfully treated cancer does not result in exclusion. 9. Contraindication to MRI scan: MRI incompatible pacemakers and metal implants, any other contraindication to MRI. For participants with possible claustrophobia, they must be willing to do the MRI with adjunct lorazepam 0.5 mg to reduce anxiety. For participants who are recruited and are eligible for MRI but are unable to complete the baseline MRI, a repeat MRI for the same time-point can be attempted if the subject is willing. Baseline MRI is required for study inclusion. 10. Regular use of crosswords or formal computerized cognitive training platforms averaging once per week or more than once per week in the past year. Eligible participants who join the trial are instructed not to do these procedures on their own during the trial, i.e., independent of the study. 11. Participation concurrently in another therapeutic clinical trial of a cognitive enhancing drug or device or procedure. 12. Geriatric Depression Scale (Short Form) score of ≥ 6.