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

October 30, 2025 updated by: Devangere P. Devanand, Columbia University
Effective, clinically meaningful treatments are lacking for patients with mild cognitive impairment (MCI), which is associated with increased risk of transition to dementia. Cognitive training represents an important therapeutic strategy. In a previous study, crossword puzzles were found to be superior to computerized cognitive training on the primary cognitive outcome and function with decreased brain atrophy. Building on these findings, this study will evaluate and compare the impact of high dose crosswords (4 puzzles per week) to low dose crosswords (1 puzzle per week) and a health education control group on the cognition and function of participants.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This study plans to enroll 240 participants with MCI: 75 at Columbia University, 60 at Duke, 60 at University of Miami, 45 at University of Washington. Participants will be randomized 1:1:1 to 4 crossword puzzles per week (high dose arm), 1 crossword puzzle per week (low dose arm), or health education (control arm). In the crossword groups, this initial intensive 12-week phase will be followed by booster sessions that will each comprise 30-minute sessions (1 or 4 sessions depending on assignment) completed over 1 week, and occur at weeks 20, 32, 42, 52, 64, and 78. In-person assessments will occur at 0, 12, 32, 52, 78 weeks. During weeks 0, 12, 32, 52, and 78, participants in the 4/week crosswords group will complete three sessions at home and the fourth in clinic, and participants in the 1/week group will complete one session in the clinic and none at home. During weeks 20, 42, and 64, participants will complete all sessions at home. The health education group will receive in-person sessions and assessments at weeks 0, 12, 32, 52, and 78 weeks, each for 30 min (same time frame as the crossword groups), and phone calls will be made, each for 30 min, at weeks 20, 42 and 64 to match the crossword groups (each 30 min). Unique features of the design: Evaluation of home-based crossword puzzles as the primary intervention; Comparison of two dose conditions to a comparison group; Health education comparison group with readings to mimic placebo in clinical trials; Stratification of random assignment by site, age, and early MCI/late MCI; Evaluation of MRI atrophy indices and plasma biomarkers of neurodegeneration (Neurofilament Light, Nfl) and Alzheimer Disease pathology (ptau-217).

Study Type

Interventional

Enrollment (Estimated)

240

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Florida
      • Miami, Florida, United States, 33136
        • Recruiting
        • University of Miami Miller School of Medicine
        • Contact:
        • Principal Investigator:
          • Philip D Harvey, PhD
    • New York
      • New York, New York, United States, 10032
        • Recruiting
        • Columbia University Irving Medical Center
        • Principal Investigator:
          • Davangere P Devanand, MD, MBBS
        • Contact:
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Recruiting
        • Duke University Medical Center
        • Contact:
        • Principal Investigator:
          • Murali Doraiswamy, MD
    • Washington
      • Seattle, Washington, United States, 98104
        • Recruiting
        • University of Washington
        • Principal Investigator:
          • Angela Hanson, MD
        • Contact:
          • Kristen Gonzalez-Farris
          • Phone Number: 206-897-6797
          • Email: kmfarris@uw.edu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Control
This sample will receive health education. The participant will read chapters from the book, "Living a Healthy Life with chronic conditions," 5th edition, by K Lorig, D Laurent, V Gonzalez, D Sobel, M Minor and M Gecht-Silver, and review chapters with the unblinded study coordinator.
Other: Cognitive Training

Participants (n=240) will be randomized to high dose crosswords, low dose crosswords, and health education at 1:1:1 ratio, stratified by site, age (< 70 and 70 years), and MCI status (early MCI and late MCI). In the two crossword puzzles conditions, after initial training to use the web-based platform, the participant will be assigned to do 12 weeks of crossword puzzles four times per week or 12 weeks of crossword puzzles once per week at home. After these 12 weeks, booster sessions will be either four or one 30-minute session(s) completed over 1 week. These booster sessions will occur at weeks 20, 32, 42, 52, 64, and 78. In-person assessments will occur at 0, 12, 32, 52, 78 weeks with one crossword puzzle session, which will count toward the booster session.

Health education will involve reading chapters in a book on common illnesses and lifestyle, and a research staff member will review these chapters at the same assessment intervals as the crossword puzzles conditions.
Active Comparator: Low Dose Crossword
This sample will receive low dose crossword training with one crossword puzzle per week during the first 12 weeks on the Cognifit web-based platform. Subsequent booster sessions will occur at 20, 32, 42, 52, 64 and 78 weeks.
Other: Cognitive Training

Participants (n=240) will be randomized to high dose crosswords, low dose crosswords, and health education at 1:1:1 ratio, stratified by site, age (< 70 and 70 years), and MCI status (early MCI and late MCI). In the two crossword puzzles conditions, after initial training to use the web-based platform, the participant will be assigned to do 12 weeks of crossword puzzles four times per week or 12 weeks of crossword puzzles once per week at home. After these 12 weeks, booster sessions will be either four or one 30-minute session(s) completed over 1 week. These booster sessions will occur at weeks 20, 32, 42, 52, 64, and 78. In-person assessments will occur at 0, 12, 32, 52, 78 weeks with one crossword puzzle session, which will count toward the booster session.

Health education will involve reading chapters in a book on common illnesses and lifestyle, and a research staff member will review these chapters at the same assessment intervals as the crossword puzzles conditions.
Active Comparator: High Dose Crossword
This sample will receive high dose crossword training. This sample will receive high dose crossword training with four crossword puzzles per week during the first 12 weeks on the Cognifit web-based platform, followed by booster sessions at 20, 32, 42, 52, 64 and 78 weeks.
Other: Cognitive Training

Participants (n=240) will be randomized to high dose crosswords, low dose crosswords, and health education at 1:1:1 ratio, stratified by site, age (< 70 and 70 years), and MCI status (early MCI and late MCI). In the two crossword puzzles conditions, after initial training to use the web-based platform, the participant will be assigned to do 12 weeks of crossword puzzles four times per week or 12 weeks of crossword puzzles once per week at home. After these 12 weeks, booster sessions will be either four or one 30-minute session(s) completed over 1 week. These booster sessions will occur at weeks 20, 32, 42, 52, 64, and 78. In-person assessments will occur at 0, 12, 32, 52, 78 weeks with one crossword puzzle session, which will count toward the booster session.

Health education will involve reading chapters in a book on common illnesses and lifestyle, and a research staff member will review these chapters at the same assessment intervals as the crossword puzzles conditions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in ADASCog-14 (14-item Alzheimer's Disease Assessment Scale - Cognitive subscale)
Time Frame: Baseline, 78 weeks
The ADASCog-14 is a brief neuropsychological assessment used to assess the severity of cognitive symptoms of dementia. It is one of the most widely used cognitive scales in clinical trials and is considered to be the "gold standard" for assessing antidementia treatments. The total score range is 0 to 90; a higher score indicates greater cognitive impairment.
Baseline, 78 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Functional Activities Questionnaire (FAQ) score
Time Frame: Baseline, 78 weeks
The FAQ is a patient-reported measure of cognitive impairment on difficulties in activities of daily living. The total score range is 0 to 30, with a higher score indicating greater impairment.
Baseline, 78 weeks
Change in MRI hippocampal volume
Time Frame: Baseline, 78 weeks
The hippocampal volume is a measurement of brain atrophy. Hippocampal volume ranges from 0 to 10 cu cm with higher values indicating large hippocampal volume. Decrease in this measure indicates hippocampal atrophy.
Baseline, 78 weeks
Change in cortical thickness
Time Frame: Baseline, 78 weeks
The cortical thickness is a measurement of brain atrophy. Values range from 0 to 1 with higher values indicating greater cortical thickness.
Baseline, 78 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Preclinical Alzheimer Composite-5 (PACC5)
Time Frame: Baseline, 78 weeks
PACC5 provides a comprehensive assessment of Alzheimer's disease-relevant cognitive impairment and to serve as a tool with validated sensitivity to detect cognitive decline over time. It is comprised of five tests: Mini-Mental State Examination (total score range 0-30), Wechsler Memory Scale-Revised Logical Memory Delayed Recall (total score range 0-25), Digit-Symbol Coding Test (total score range 0-93), Free and Cued Selective Reminding Test Free + Total Recall (total score range 0-96), and Category Fluency Test (graded by number of correct words belonging in the categories of animals, fruits, and vegetables; not graded on a scale). The PACC5 is computed as an averaged z-score of all five tests.
Baseline, 78 weeks
Change in Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL-PI)
Time Frame: Baseline, 78 weeks

The range of scores of the 15 items ADL question is 0-45 with higher scores indicating better performance. This is the outcome measure.

In addition, there is a range of scores for the 5 items of physical function questions, which is 0-5 with higher scores indicating intact physical functioning.
Baseline, 78 weeks
plasma neurofilament light and ptau 217
Time Frame: Baseline, 78 weeks

Evaluate change in biomarkers over 78 weeks in the two crosswords groups and health education control group.

Range = 0-999 ng/ml with higher values indicating more brain pathology.
Baseline, 78 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Columbia University

Collaborators

National Institute on Aging (NIA)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 17, 2024

Primary Completion (Estimated)

February 28, 2029

Study Completion (Estimated)

February 28, 2029

Study Registration Dates

First Submitted

September 16, 2024

First Submitted That Met QC Criteria

September 16, 2024

First Posted (Actual)

September 19, 2024

Study Record Updates

Last Update Posted (Estimated)

October 31, 2025

Last Update Submitted That Met QC Criteria

October 30, 2025

Last Verified

June 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AAAU9623
  • 2R01AG052440-06A1 (U.S. NIH Grant/Contract)
  • WCG 20240282 (Other Identifier: Western-Copernicus Group (WCG) Institutional Review Board)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified participant data for all measures will be shared among investigators in the study.

IPD Sharing Time Frame

From October 15, 2024 until September 30, 2029

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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