Computerized Games versus Crosswords Training in Mild Cognitive Impairment
Abstract
Background
Mild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in patients with MCI is unclear.
Methods
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.
Results
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]).
Conclusions
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.)
Introduction
In older adults, mild cognitive impairment (MCI) confers increased risk of progression to dementia, particularly Alzheimer’s disease.1 A cognitively active lifestyle may decrease the risk of cognitive decline and dementia. A systematic review of 22 population-based studies estimated that complex mental activities, such as reading books, playing checkers, and completing crosswords or other puzzles, reduced overall incident dementia risk by 46% during a median 7-year period.2 In a trial of in-person, small-group cognitive training of more than 2,800 cognitively intact participants, cognitive improvement was associated with improved instrumental activities of daily living in participants who completed reasoning or speed-of-processing training, but not memory training, compared with a no-contact control group.3,4 Several of these improvements were maintained at 10-year follow-up.4
Computerized cognitive training (CCT) with cognitive exercises has demonstrated benefit in healthy adults and people with psychiatric disorders.5-8 Among older adults with MCI, a meta-analysis examining CCT showed statistically significant improvements in cognitive outcomes, but with considerable variability in the type of improvement observed in global cognition, learning, memory, and attention, and less consistent effects on functioning.9 Few studies of CCT in MCI have demonstrated a significant effect on functional abilities.10 In patients with dementia, however, the efficacy of CCT is not established. Patients may have difficulty comprehending the cognitive training tasks, resulting in poor compliance.9,11 In addition, CCT may have neuroplastic effects in specific brain regions, including the hippocampus.12-16
Computerized crossword puzzles have been evaluated in several studies. In an 8-week trial in patients with heart failure, computerized crossword puzzles, CCT, and usual-care interventions showed similar effects on cognitive outcomes, although all groups also received a nurse-enhanced intervention, making the relative contribution of the other interventions unclear.17 In a randomized trial of computerized interventions, visual speed of processing training led to worse cognitive and quality-of-life outcomes than did crossword puzzles in participants in assisted living, many of whom were cognitively impaired.18 These studies suggest that crossword puzzle training may have cognitive-enhancing effects in physically and cognitively impaired individuals.
We compared the efficacy of computerized training with Web-based cognitive games with computerized training with crossword puzzles among adults with MCI in the two-site, 78-week COG-IT (Cognitive Training and Neuroplasticity in Mild Cognitive Impairment) trial.19 Because games have demonstrated efficacy in cognitively intact older individuals, we hypothesized that games would also show superior efficacy to crosswords in cognitive and functional outcomes in patients with MCI.
Methods
Trial Design and Oversight
The study design and methods were published previously.19 The study was conducted at two sites: Columbia University/New York State Psychiatric Institute (New York; Columbia University was the lead coordinating site) and Duke University Medical Center (Durham, NC). The sites’ institutional review boards approved the study, which was funded by the National Institute on Aging. Lumos Labs provided specific games and crossword training modules with technical support from their Web-based platform without cost and had no role in study design, data interpretation, or publication. Participants were not charged but had no poststudy commitment. A data and safety monitoring board provided oversight. The protocol is available with the full text of this article at evidence.nejm.org.
Trial Participants
Participants were recruited from clinical referrals, supplemented by advertising. All participants signed the informed consent form, which indicated random assignment to one of two cognitively stimulating exercises — Web-based cognitive games or computerized crossword puzzles — without stating which treatment might be better. Key inclusion criteria were aged 55 to 95 years, English-speaking ability, and meeting Alzheimer’s Disease Neuroimaging Initiative criteria for early MCI or late MCI. Early MCI was defined by a Wechsler Memory Scale-III Logical Memory delayed recall score (scores range from 0 to 25, with higher scores indicating better verbal recall) of 3 to 6 with 0 to 7 years of education, score of 5 to 9 with 8 to 15 years of education, and score of 9 to 11 with 16 or more years of education. Late MCI was defined by a Wechsler Memory Scale-III Logical Memory delayed recall score of ≤2 with 0 to 7 years of education, score of ≤4 with 8 to 15 years of education, and score of ≤8 with 16 or more years of education. Additional inclusion criteria were a Folstein Mini-Mental State Examination score of ≥23 of 30 (range, 0 to 30; a higher score indicates better cognition) and availability of an informant, such as a family member, to provide information about the participant’s functioning. Participants were required to have a home computer with Internet connection to access the study website. Key exclusion criteria were current major psychiatric or neurologic disorder, dementia, contraindication to magnetic resonance imaging (MRI; conducted on 3.0 T scanners), and use of online cognitive games or crossword puzzles two times per week or more in the past year. Prescribed cholinesterase inhibitors and memantine were continued. Use of high-dose opioids, anticholinergics, and/or benzodiazepines in lorazepam equivalents of ≥1 mg per day were also exclusion criteria. Inclusion and exclusion criteria are described in more detail in Table S1 of the Supplementary Appendix available with the full text of this article at evidence.nejm.org.
Randomization and Treatment
Patients were randomly assigned 1:1 to games or crosswords, stratified by site, age (≤70 and >70 years), and early MCI versus late MCI. An unblinded research coordinator conducted training sessions, and a blinded research coordinator administered cognitive and functional assessments. Participants were unblinded.
Games and Crosswords
Lumos Labs provided Web-based cognitive games and crossword puzzles. Lumos Labs account credentials included a study-specific email address and password. Each games session was composed of 6 modules randomly selected from 18 available modules that included memory tasks, matching tasks, spatial recognition tasks, and processing speed tasks. For games, difficulty was scaled over time using the participant’s Lumosity Performance Index, which considered three variables: games performance, cognitive area performance, and overall cognitive performance.19 Participants received their overall games performance score at the end of each session. Lumos Labs also provided computerized crossword puzzles of medium difficulty — intended to be equivalent to the New York Times’ Thursday crossword puzzles — without performance-based scaling over time. If the puzzle was completed within 15 of the allotted 30 minutes, a second puzzle was presented. The participant could view the correct answers at the end of the session but did not receive a score.
Participants were evaluated in person at five scheduled visits (weeks 0, 12, 32, 52, and 78), and research staff conducted three additional scheduled phone calls (weeks 20, 42, and 64). Figure S1 describes the timeline of the study. Initial intensive, home-based computerized training for games or crosswords consisted of four 30-minute training sessions per week for 12 weeks. Subsequent booster training was composed of four 30-minute sessions, completed over 1 week and occurring at weeks 20, 32, 42, 52, 64, and 78. During weeks 32, 52, and 78, participants completed three sessions at home and the fourth in clinic. During weeks 20, 42, and 64, participants completed all four sessions at home. Unblinded study coordinators received weekly electronic reports of completed sessions and contacted participants who had not completed sessions to attempt to improve adherence.
Outcomes
The primary outcome was change from baseline in the 11-item Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) total score20 at 78 weeks, adjusted for baseline. Scores on ADAS-Cog range from 0 to 70, with higher scores indicating greater cognitive impairment. The secondary cognitive outcome was the change from baseline in composite z score of neuropsychological tests at 78 weeks, adjusted for baseline. Lumosity software support for the Neurocognitive Performance Test (NCPT),21 used for one of the secondary cognitive outcomes, was discontinued halfway through the study; therefore, this measure was not analyzed.
Additional secondary outcomes at 78 weeks included the short-form University of California, San Diego Performance-Based Skills Assessment (UPSA) score (range, 0 to 100; higher scores indicate better functional performance), a performance-based measure of skills to organize, plan, and perform such tasks as counting physically presented change with bills and coins or planning a trip22; the informant-reported Functional Activities Questionnaire (FAQ) score (range, 0 to 30; higher scores indicate greater impairment in instrumental activities of daily living) with items that include paying bills, shopping, remembering appointments, and taking medications23; and the proportion of participants transitioning from MCI to clinical dementia.
Hypothesized moderators of outcome were apolipoprotein E e4 genotype, baseline MRI hippocampal volume, and baseline University of Pennsylvania Smell Identification Test.24 Exploratory analyses were conducted for change from baseline to week 78 in hippocampal volume (mean total volume), calculated as the summation of right and left hippocampal volumes, and cortical thickness, evaluated with Freesurfer version 6.0 from the MRI three-dimensional spoiled gradient recalled acquisition. Resting-state functional MRI results with changes in default mode network connectivity25 and related measures will be reported separately from this article.
Statistical Analysis and Sample Size
Demographics and baseline values were compared between treatment arms using Wilcoxon’s rank-sum test for continuous variables and Fisher’s exact test for categorical variables. We conducted linear mixed-effects model repeated-measures analysis to assess the effect of treatment on cognitive and functional outcomes. For each outcome, the change in the measure (baseline minus study time point) was the dependent measure, and treatment, study time point, and their interaction were the predictors, adjusting for the baseline value of the outcome measure. The model was then further adjusted for the stratification factors of site, age group, and MCI type. Each model included all time points, with a focus on 12 weeks (end of intensive training sessions) and 78 weeks (primary end point). Effects of treatment on change in MRI outcomes (week 0 to week 78) were evaluated in linear regression models.
Hypothesized moderators were assessed individually by including the moderator variable and the associated moderator–interaction terms in regression models (week 0 to week 78). Fisher’s exact test was used to test the association between the binary outcome of dementia and treatment group, and the associations between adverse events and treatment group.
Sample Size
A sample size of 100 participants was projected to detect a Cohen’s d effect size of 0.58 (medium effect size) with 80% power for the primary outcome, assuming dropout was uniformly distributed over time to reach 20% by 78 weeks. On the basis of the data and safety monitoring board recommendation to balance site demographics, the projected sample size was increased to 110.
Analyses were conducted on the intent-to-treat sample (i.e., all randomly assigned participants) according to the assigned treatment. Missing data on outcome variables were addressed by linear mixed-effects models, which do not require complete measurements under the assumption that the data were missing at random. Two-sided α<0.05 was the criterion for significance for the primary outcome.19 For secondary outcomes, there was no adjustment for multiple statistical comparisons; point estimates with unadjusted 95% confidence intervals (CIs) are reported.
Results
Participant Characteristics
Between November 2017 and February 2020, 168 participants were screened for eligibility. Enrollment ended in March 2020 because of pandemic restrictions. Of 109 enrolled participants, 2 dropped out before random assignment (Fig. 1), and the final sample included 107 randomly assigned participants. The last study visit occurred in September 2021. The mean age of participants was 71.2 years (SD, 8.8 years), and 58% were female. Demographics were similar to the general population of people with MCI and included 25% minority populations (Table S2). Participants assigned to games and crosswords did not differ in demographics and baseline measures (Table 1); therefore, only the three stratification factors were examined as covariates. During the study, 9 (17.6%) of 51 participants dropped out in the games group compared with 7 (12.5%) of 56 participants in the crosswords group. Among late MCI participants, 6 (20.0%) of 30 dropped out in the games group and 5 (15.2%) of 33 dropped out in the crosswords group.
Figure 1

CONSORT Diagram.
Participants with mild cognitive impairment were randomly assigned to games or crossword puzzles for 78 weeks.
Table 1

Patient Characteristic | Games (n=51) | Crosswords (n=56) |
---|---|---|
Male — no. (%) | 17 (33.3) | 28 (50.0) |
Age — yr | 71.1 (±8.5) | 71.3 (±9.1) |
Education — yr | 16.6 (±3.0) | 16.8 (±3.3) |
Race — no. (%) | ||
White | 39 (76.5) | 42 (75.0) |
Black | 11 (21.6) | 13 (23.2) |
Latino | 1 (2.0) | 3 (5.4) |
Other | 1 (2.0) | 1 (1.8) |
Stratum for randomization — no. (%) | ||
Age≤70 yr with early MCI | 10 (19.6) | 11 (19.6) |
Age≤ 70 yr with late MCI | 12 (23.5) | 14 (25.0) |
Age>70 yr with early MCI | 11 (21.6) | 12 (21.4) |
Age>70 yr with late MCI | 18 (35.3) | 19 (33.9) |
Columbia site — no. (%) | 28 (54.9) | 27 (48.2) |
Apolipoprotein E e4 positive — no. (%) | 26 (51.0) | 21 (37.5) |
MMSE total score | 27.1 (±1.6) | 26.8 (±1.7) |
ADAS-Cog total score | 9.5 (±3.5) | 9.6 (±3.5) |
Neuropsychological composite z-score | −0.1 (±1.0)† | 0.1 (±1.0)‡ |
UPSA total score | 80.6 (±10.9) | 81.5 (±11.4) |
FAQ total score | 3.4 (±4.1) | 3.2 (±3.9) |
UPSIT total score | 27.9 (±8.1)§ | 28.5 (±7.2) |
MRI hippocampal volume — mm3 | 2987 (±415.3)§ | 3083 (±385.8)¶ |
MRI cortical thickness — mm | 2.4 (±0.1)‖ | 2.3 (±0.1)** |
Oral cholinesterase inhibitor use — no. (%) | 7 (13.7) | 7 (12.5) |
Memantine use — no. (%) | 1 (2.0) | 2 (3.6) |
Baseline Characteristics of Participants with Mild Cognitive Impairment by Randomized Treatment Group.*
*
Plus–minus values are means ±SD. Early mild cognitive impairment (MCI) was defined as Wechsler Memory Scale-III (WMS-III) Logical Memory delayed recall score (scores range from 0 to 25, with higher scores indicating better verbal recall) of 3 to 6 with 0 to 7 years of education, score of 5 to 9 with 8 to 15 years of education, and score of 9 to 11 with 16 or more years of education. Late MCI was defined as WMS-III Logical Memory delayed recall score of ≤2 with 0 to 7 years of education, score of ≤4 with 8 to 15 years of education, and score of ≤8 with 16 or more years of education. Neuropsychological composite is a z score composite of 11 tests in the diagnostic neuropsychological assessment. Higher scores indicate better cognitive performance. ADAS-Cog denotes Alzheimer’s Disease Assessment Scale–Cognitive Subscale 11 (score range, 0 to 70; higher scores indicate greater cognitive impairment); FAQ, Functional Activities Questionnaire (score range, 0 to 30; higher scores indicate greater impairment in instrumental activities of daily living); MMSE, Mini Mental Status Examination (Folstein, range 0 to 30; higher score indicates better cognition); MRI, magnetic resonance imaging; UPSA, University of California San Diego Performance-Based Skills Assessment short form (score range, 0 to 100; higher scores indicate better functional performance); and UPSIT, University of Pennsylvania Smell Identification Test (range, 0 to 40; higher score indicates better odor identification).
†
n=49.
‡
n=55.
§
n=50.
¶
n=54.
‖
n=45.
**
n=52.
Cognitive Outcomes
Over 78 weeks, ADAS-Cog score, which was adjusted for baseline ADAS-Cog score, showed a small decline for games and an improvement for crosswords (LS means difference, −1.44 points; 95% CI, −2.83 to −0.06; P=0.04; Table 2). ADAS-Cog scores worsened by an average of 0.4 points in the games group (9.53 to 9.93) and improved by nearly 1 point in the crosswords group (9.59 to 8.61; Table S3). At week 12, ADAS-Cog score showed a similar LS means difference of −1.35 points (95% CI, −2.71 to 0.00). Compared with the games group, the Cohen’s d effect size for crossword puzzles for change in ADAS-Cog scores from baseline was 0.43 (consistent with a medium effect size) at week 12 and 0.34 (consistent with a small effect size) at week 78 (Fig. 2).
Figure 2

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

Outcome Measure | No. of Participants | No. of Participants | Baseline Adjusted, Change from Baseline Least Squares Mean (±SE) | Baseline Adjusted, Change from Baseline Least Squares Mean (±SE) | Least Squares Mean Treatment Difference (95% CI) | P Value by Mixed-Model Analysis |
---|---|---|---|---|---|---|
Games Baseline (n=51) | Crosswords Baseline (n=56) | Games | Crosswords | |||
Primary outcome | ||||||
ADAS-Cog at 78 wk | 44 | 51 | −0.89 (±0.51) | 0.55 (±0.48) | −1.44 (−2.83 to −0.06) | 0.04 |
Secondary outcomes | ||||||
ADAS-Cog | ||||||
12 wk | 46 | 55 | −0.31 (±0.51) | 1.05 (±0.47) | −1.35 (−2.71 to 0.00) | |
78 wk with covariates | 44 | 51 | −0.89 (±0.49) | 0.57 (±0.45) | −1.46 (−2.78 to −0.15) | |
Neuropsychological composite | ||||||
12 wk | 43 | 54 | −0.24 (±0.08) | −0.18 (±0.07) | −0.06 (−0.27 to 0.14) | |
78 wk | 42 | 50 | −0.24 (±0.08) | −0.27 (±0.07) | 0.03 (−0.18 to 0.24) | |
78 wk with covariates | 42 | 50 | −0.23 (±0.08) | −0.27 (±0.07) | 0.04 (−0.17 to 0.25) | |
UPSA | ||||||
78 wk | 44 | 51 | 0.55 (±1.23) | −0.99 (±1.44) | 1.55 (−1.78 to 4.88) | |
78 wk with covariates | 44 | 51 | 0.76 (±1.20) | −1.14 (±1.11) | 1.89 (−1.35 to 5.13) | |
FAQ | ||||||
12 wk | 46 | 55 | −0.39 (±0.33) | −0.02 (±0.30) | −0.37 (−1.24 to 0.51) | |
78 wk | 43 | 52 | −2.00 (±0.34) | −0.92 (±0.31) | −1.08 (−1.97 to −0.18) | |
78 wk with covariates | 43 | 52 | −2.07 (±0.32) | −0.89 (±0.29) | −1.18 (−2.04 to −0.33) |
Analyses of Efficacy Outcomes for Games Versus Crosswords.*
*
Confidence intervals (CIs) have not been adjusted for multiplicity; therefore, CIs should not be used to reject or not reject treatment effects. Results of linear mixed-effects model repeated-measures analysis are presented in the table. Change in ADAS-Cog and Functional Assessment Questionnaire (FAQ) were analyzed as week 0 minus week 78, adjusting for baseline value of the corresponding measure. For these two measures, a negative difference score indicates worsening and a positive difference score indicates improvement. Changes in neuropsychological composite and UPSA score were analyzed as week 0 minus week 78, adjusting for baseline value of the corresponding measure. For these two measures, a negative difference score indicates improvement and a positive difference score indicates worsening. The three stratification variables were included together as covariates for the analyses with covariates: site (Columbia vs. Duke), age≤70 versus >70 years, early MCI versus late MCI. ADAS-Cog was completed at weeks 0, 12, 52, 78 (scoring range, 0 to 70). Higher scores indicate greater cognitive impairment. Neuropsychological composite is a z score composite of 11 tests in the diagnostic neuropsychological assessment done at weeks 0, 12, 52, and 78. Higher scores indicate better cognitive performance. UPSA was done at weeks 0, 32, and 78 (score range, 0 to 100). Higher scores indicate better functional performance. FAQ was administered to the informant at 0, 12, 20, 32, 52, and 78 weeks (score range, 0 to 30). Higher scores indicate greater impairment in instrumental activities of daily living. Alzheimer’s Disease Assessment Scale–Cognitive Subscale 11 (ADAS-Cog), neuropsychological test battery, and University of California San Diego Performance-Based Skills Assessment (UPSA) were administered at a limited number of time points to reduce practice effects.
Improvement of ≥2 points in ADAS-Cog score was observed in 25.0% of the games group and in 37.3% of the crosswords group at 78 weeks. Within the late MCI group, change in ADAS-Cog score worsened for games and improved for crosswords at week 12 (LS means difference, −1.92; SE, 0.85; 95% CI, −3.6 to −0.23) and week 78 (LS means difference, −2.45; SE, 0.89; 95% CI, −4.21 to −0.70), but this effect was not observed in early MCI (change in ADAS-Cog score at week 12: LS means difference, −0.26; 95% CI, −2.31 to 1.80; and at week 78: LS means difference, 0.28; 95% CI, −1.78 to 2.35). There was no treatment by site interaction for the primary outcome. Change in composite neuropsychological test score was similar in the two groups (Table 2 and Fig. 3).
Figure 3

Change in Secondary Cognitive and Functional Outcomes Over Time for Participants Randomly Assigned to Games and Crossword Puzzles, Adjusted for Baseline Values.
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.
In a sensitivity analysis using analysis of covariance, results (point estimates) were similar to the primary mixed-model analysis, although the 95% CIs for ADAS-Cog included the null, with slight inflation of the SE (Table S5). Furthermore, in analyses that assessed the adequacy of the fitted mixed-effects models, the residual plots did not show a systematic pattern, indicating no obvious violation from the underlying assumptions in mixed-effects models.
None of the three prespecified potential moderators — apolipoprotein E e4 genotype, baseline hippocampal volume, and baseline University of Pennsylvania Smell Identification Test — affected the change in ADAS-Cog score.
Functional Outcomes
Change in UPSA score, adjusted for baseline UPSA score, did not differ between the games and crosswords groups (Table 2 and Fig. 3). Change in FAQ score, adjusted for baseline FAQ score, was greater for the games group than for the crosswords group at week 78 (LS means difference, −1.08 points; 95% CI, −1.97 to −0.18; Table 2 and Fig. 3), even after adjusting for covariates in the model (LS means difference, −1.18 points; 95% CI, −2.04 to −0.33; Table 2). For change in FAQ score, effects were similar for young versus old participants, early MCI versus late MCI, and the two sites. FAQ raw scores are described in Table S3.
Compliance and Site by Treatment Effect
Some participants exceeded the targeted number of enrolled sessions (intended maximum, 72; actual maximum observed, 116) because of the expanded time windows between in-person assessments, particularly during pandemic-related delays. The total number of enrolled sessions was similar for games versus crosswords, young versus old participants, and early MCI versus late MCI. Participants at Duke enrolled in more sessions than at Columbia (median, 72; interquartile range, 64 to 74, vs. median, 68; interquartile range, 66 to 75 sessions per participant; Hodges-Lehmann estimate of location difference, 3; 95% CI, 0 to 6). The coronavirus disease 2019 pandemic led to delays of ≥60 days for in-person testing during the trial in 6.3% of participants (7.3% games; 5% crosswords).
Progression to Dementia
Progression to a diagnosis of dementia occurred in 6 (10.7%) of 56 participants in the crosswords group and 8 (15.7%) of 51 in the games group (odds ratio, 0.65; 95% CI, 0.17 to 2.32). Reversion from MCI to normal cognition occurred in 17 (30.4%) of 56 participants in the crosswords group and 12 (23.5%) of 51 in the games group (odds ratio, 1.41; 95% CI, 0.55 to 3.71).
MRI Brain Changes
Decline in hippocampal volume at week 78, adjusted for baseline hippocampal volume, was greater for the games group than for the crosswords group after adjusting for the three stratification variables (LS means difference, 34.07; SE, 17.12; 95% CI, 0.51 to 67.63). Decline in cortical thickness at week 78, adjusted for baseline cortical thickness, was greater for the games group after adjusting for the three stratification variables (LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04).
Adverse Events
The number and type of adverse events, including serious adverse events, for the treatment groups are described in Table S4. None was considered to be related to treatment conditions. Coronavirus disease 2019 diagnosis occurred in 5 of 51 participants in the games group and 0 of 56 participants in the crosswords group; its inclusion as a covariate did not change ADAS-Cog score results.
Discussion
In this 78-week, randomized comparison of computerized cognitive games versus computerized crossword puzzles, crossword puzzles showed superior efficacy to games in the cognitive outcome (ADAS-Cog), with a small-to-medium effect size. Results were similar using analysis of covariance instead of the linear mixed-model analysis. Common directionality, which is considered important in Alzheimer’s dementia clinical trials,26 was observed in the primary outcome of ADAS-Cog (cognitive) score and the secondary outcomes of FAQ (function) score and changes in the structural MRI measures of hippocampal volume and cortical thickness (neurodegenerative), but not in the UPSA or neuropsychological composite scores. A lack of effect on the traditional neuropsychological measures may be because they were not developed specifically to measure change in MCI.
These results were unexpected and in opposition to the proposed hypotheses. The choice of games was based on experience from a large data set of online games that was selected for feasibility and targeted to improve memory and executive ability. In the late MCI group, change in ADAS-Cog score showed a decline for the games group versus improvement for the crosswords group. Participants with late MCI may have found the games too difficult to comprehend and execute satisfactorily. In contrast, most older adults are familiar with crossword puzzles, which were of medium difficulty in the trial and allowed participants to set their own pace.
In a previous online 10-week study of cognitively intact individuals aged 18 to 80 years, cognitive training with games (Lumos Labs, consisting of 45 modules played for 15 minutes daily) was superior to computerized crosswords on a population-normed NCPT composite score and a self-rated outcome, although both groups showed improvements.27,28 The discrepant results between this trial and the earlier online Lumos Labs studies may be related to differences in study samples in age range (55 to 95 years vs. 18 to 80 years), diagnosis (MCI vs. cognitively intact individuals), in-person versus online testing, training modules, training schedule, long-term versus short-term assessment, and outcomes. It is possible that games are superior in cognitively intact individuals, especially in young adults who are familiar with games, but the more familiar and less technical crossword puzzles may be superior in cognitively impaired older individuals. Another possibility is that both treatments may have been efficacious if they had been compared with a control condition. As no single trial is definitive, the positive results in this investigation need confirmation in an independent sample.
There is a lack of consensus regarding the minimum clinically important difference for the ADAS-Cog score in individuals with MCI. In this trial, the magnitude of the mean difference between crossword puzzles and games in ADAS-Cog change scores was 1.38 points, with 37.3% of patients in the crosswords group and 25.0% of patients in the games group showing mean ADAS-Cog improvement of ≥2 points. In pivotal placebo-controlled trials of cholinesterase inhibitors and memantine for the treatment of Alzheimer’s dementia, a mean difference of approximately 2 points favoring drug over placebo provided the basis for regulatory approval. Across published clinical trials, the mean advantage over placebo for donepezil, a widely prescribed cholinesterase inhibitor, was 2.67 points on the ADAS-Cog.29 Because this trial did not include a control group that would be equivalent to placebo, the magnitude of the effect for crossword puzzles compared with a control group should be determined in a future trial.
The limited investigation of crossword puzzles as a digital cognitive-enhancing intervention may be explained by its typical evaluation as a control group rather than as a targeted cognitive-enhancing strategy.17,18,30 Participants showed less decline in instrumental activities of daily living with crosswords than with games, suggesting that clinically relevant cognitive improvement in a cognitive measure (ADAS-Cog score) was associated with functional change (FAQ score).
After adjusting for stratification variables, decreases in MRI hippocampal volume and cortical thickness were smaller with crosswords than with games, suggesting a possible disease-modifying effect. In cognitively healthy middle-aged to older adults, memory training has been associated with increased cortical thickness, especially in the right fusiform and lateral orbitofrontal cortex.31 Mechanisms underlying the therapeutic effects of crossword puzzle training need additional investigation.
The strengths of the study include the diverse sample, the rigorous methodology with blinded assessment of outcomes, the high degree of protocol adherence with a dropout rate in line with expectations, and the long study duration to examine persistent effects.5-8,32-35 The representativeness of the sample, including 25% minority participation, supports applying the results to the general MCI population. The computerized platform allowed for weekly monitoring of compliance in home-based training for both treatments and provided real-time feedback on performance in the games condition. The consent form described the two treatments without mentioning which might be better. This feature may have improved participant engagement in contrast to studies in which crossword puzzles were stated to be the control comparison.
Limitations include the average high level of education that restricts generalizability, absence of a control condition without cognitive training, use of different 3.0 T MRI scanners, and discontinuation of the NCPT midway through the trial. During the pandemic, most participants completed booster sessions at home without in-person clinic training sessions.
In summary, home-based computerized crossword puzzle training was associated with improved cognition compared with computerized games in participants with MCI. If these effects are replicated and expanded in future trials with the inclusion of a control group that does not receive cognitive training, crossword puzzle training could become a home-based, scalable, cognitive enhancement tool for individuals with MCI.
Notes
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.
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Published online: October 27, 2022
Published in issue: November 22, 2022
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