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Computerized Games versus Crosswords Training in Mild Cognitive Impairment

  • D. P. Devanand, M.D.1,2,
  • Terry E. Goldberg, Ph.D.1,2,3,
  • Min Qian, Ph.D.4,
  • Sara N. Rushia, B.A.5,6,
  • Joel R. Sneed, Ph.D.1,2,3,5,
  • Howard F. Andrews, Ph.D.2,
  • Izael Nino, B.A.1,2,
  • Julia Phillips, B.A.1,2,
  • Sierra T. Pence, B.S.7,
  • Alexandra R. Linares, B.S.7,
  • Caroline A. Hellegers, M.A.7,
  • Andrew M. Michael, Ph.D.8,
  • Nancy A. Kerner, M.D.1,2,
  • Jeffrey R. Petrella, M.D.9, and
  • P. Murali Doraiswamy, M.B.B.S.7,8,10
Published October 27, 2022
NEJM Evid 2022; 1 (12)



Mild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in patients with MCI is unclear.


In a two-site, single-blinded, 78-week trial, participants with MCI — stratified by age, severity (early/late MCI), and site — were randomly assigned to 12 weeks of intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles, followed by six booster sessions. In mixed-model analyses, the primary outcome was change from baseline in the 11-item Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) score, a 70 point scale in which higher scores indicate greater cognitive impairment at 78 weeks, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score, University of California San Diego Performance-Based Skills Assessment (functional outcome) score, and Functional Activities Questionnaire (functional outcome) score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed.


Among 107 participants (n=51 [games]; n=56 [crosswords]), ADAS-Cog score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, −1.44; 95% confidence interval [CI], −2.83 to −0.06; P=0.04). From baseline to week 78, mean ADAS-Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, −2.45; SE, 0.89; 95% CI, −4.21 to −0.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, −1.08; 95% CI, −1.97 to −0.18). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI, 0.51 to 67.63 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04 [cortical thickness]).


Home-based computerized training with crosswords demonstrated superior efficacy to games for the primary outcome of baseline-adjusted change in ADAS-Cog score over 78 weeks. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.)

A data sharing statement provided by the authors is available with the full text of this article.

Supported by National Institutes of Health, National Institute on Aging Grant Number 1R01AG052440. Lumos Labs provided the computerized Web-based platform at no cost and was not involved in the final design, analyses, or drafting of the manuscript.

Disclosure forms provided by the authors are available with the full text of this article.

We thank all the participants and their informants in the trial. We thank Jessica D’Antonio, Laura Simon-Pearson, Charlie Ndouli, and Kaylee Bodner for their assistance in data collection and conduct of the study. We thank Dr. William McDonald of Emory University, Dr. Anand Kumar of University of Illinois, and Dr. Stephen Rapp of Wake Forest University for their valuable oversight as members of the data and safety monitoring board. We thank Lumos Labs for providing the computerized Web-based platform for the interventions in this trial.

Dr. Devanand can be contacted at [email protected] or at New York State Psychiatric Institute, 1051 Riverside Drive, Unit 126, New York, NY 10032.


  • Figure 1. CONSORT Diagram.
    Figure 1

    Participants with mild cognitive impairment were randomly assigned to games or crossword puzzles for 78 weeks.

  • Figure 2. Change in 11-Item ADAS-Cog Score Over Time for Participants Randomly Assigned to Games and Crossword Puzzles, Adjusted for Baseline.
    Figure 2

    Alzheimer’s Disease Assessment Scale for Cognition (ADAS-Cog) is an 11-item scale with scoring ranging from 0 to 70. Higher scores indicate greater cognitive impairment. For ADAS-Cog, least squares mean±SE from linear mixed-effects model analysis for change from baseline, adjusted for baseline ADAS-Cog, is represented on the y-axis. A positive difference score (week 0 minus week 12 or week 52 or week 78) indicates improvement and a negative difference score indicates worsening. *P=0.04 refers to the comparison between crosswords and games from baseline to week 78.

  • Figure 3. Change in Secondary Cognitive and Functional Outcomes Over Time for Participants Randomly Assigned to Games and Crossword Puzzles, Adjusted for Baseline Values.
    Figure 3

    Panel A shows the change in Functional Assessment Questionnaire (FAQ) score over time. FAQ was administered to the participant at 0, 12, 20, 32, 52, and 78 weeks, with scoring ranging from 0 to 30. Higher scores indicate greater impairment in instrumental activities of daily living. Panel B shows the change in University of California San Diego Performance Skills Assessment (UPSA) score. UPSA was administered at weeks 0, 32, and 78, with scoring ranging from 0 to 100. Higher scores indicate better functional performance. Panel C shows the change in neuropsychological composite score. The neuropsychological composite score represents a z score composite of 11 tests in the diagnostic neuropsychological assessment and was administered at weeks 0, 12, 52, and 78. Higher scores indicate better cognitive performance. For each measure, least squares mean±SE from linear mixed-effects model analysis for change from baseline to the specified time point, adjusted for baseline value of the measure, is represented on the y-axes.

  • Table 1. Baseline Characteristics of Participants with Mild Cognitive Impairment by Randomized Treatment Group.
  • Table 2. Analyses of Efficacy Outcomes for Games Versus Crosswords.