Comparative Effectiveness of Behavioral Interventions to Prevent or Delay Dementia (CEBIPODD)
Phase: NA
Conditions: Mild Cognitive Impairment, Memory Disorders, Mild Dementia, Impaired Cognition, Mild Cognitive Disorder, Amnestic Disorder, Dementia and Amnestic Conditions, Poor Short-term Memory, Memory Impairment
Sponsor: Mayo Clinic

Behavioral Interventions to Prevent or Delay Dementia 
NCT02265757 
08/01/2018 
 

Behavioral Interventions to Prevent or Delay Dementia 
 
Melanie Chandler, PhD1; Dona E.C. Locke, PhD2; Julia E. Crook, PhD3; Julie A. Fields, PhD4; 
Colleen S. Thomas, MS3; Vaishali Phatak, PhD5; Pam Dean PhD6; Glenn E. Smith, PhD7 
 
 
Correspondence and Reprints: Melanie J. Chandler, PhD; Division of Psychology, Mayo Clinic, 
4500 San Pablo Rd; Ph: 904-953-6600; Fax: 904-953-0461; Email: chandler.melanie@mayo.edu 
 
 
Support: Research reported in this manuscript was primarily funded through a Patient-Centered 
Outcomes Research Institute (PCORI) Award (CER-1306-01897). The statements in this 
publication are solely the responsibility of the authors and do not necessarily represent the views 
of the Patient-Centered Outcomes Research Institute (PCORI), its Board of Governors or 
Methodology Committee. 
 
Trial registration: ClinicalTrials.gov Identifier: NCT02265757 
 
IRB: Institutional Review Boards at the Mayo Clinic (14-000885) and University of Washington 
(49235) 
 

Abstract 
Importance:  A 2017 National Academies of Sciences Engineering and Medicine (NAS) report 
suggests that certain behavioral interventions show promise as strategies for delaying or 
preventing dementia but require a stronger evidence base. 
Objective:  To examine five behavioral interventions’ effectiveness at impacting the outcomes of 
highest importance to persons with mild cognitive impairment (pwMCI).  
Design:  Multi-site cluster randomized, multi-component comparative effectiveness trial.  
Participants: Two-hundred seventy two pwMCI and their partners were enrolled. PwMCI met 
prevailing National Institute on Aging-Alzheimer Association for MCI with memory 
impairment. Partners were cognitively normal and had frequent contact with the pwMCI. 
Interventions: The intervention program was modeled on the Mayo Clinic HABIT program, a 
10-day, 50-hour group intervention including memory compensation training, computerized 
brain fitness, yoga, patient and partner support groups and wellness education. In the present 
comparative effectiveness study, one of 5 interventions was selected by block randomization to 
be withheld for each group. Dyads were followed to 12 months post-intervention with a one-day 
booster session occurring at 6 months. 
Outcomes: Primary outcome measures were selected based on the preference rankings of 
previous HABIT completers. All measures were focused on pwMCI at one year of follow-up. 
Measures included validated scales of quality of life (QOL), mood, self-efficacy and memory 
based-activities of daily living (mADL).  
Results: Wellness Education had the greatest estimated impact on QOL. Mood and self-efficacy 
were most positively impacted by a combination of wellness education, yoga, compensation 

based calendar training (the MSS) and supportive group therapy. Memory ADLs were most 
negatively affected by lack of physical exercise. All effect sizes were modest.  
Conclusion and Relevance: The findings provide further support for behavioral interventions and 
extend our preliminary comparative effectiveness finding showing MSS to be superior to brain 
fitness exercises for mADLs. As might be expected, different outcomes are optimized by 
different combinations of interventions. The findings serve as a preliminary foundation for 
personalized approaches to behavioral interventions for pwMCI and that comport which each 
individuals priority outcomes. 
Trial Registration: ClinicalTrials.gov Identifier: NCT02265757 
 
 
 
 
 
Keywords (3-6): nonpharmacological interventions; behavioral interventions; cognitive 
intervention; MCI, caregiver; patient preferences 
 
 
 

Introduction 
As a medical community, we are increasingly able to identify Alzheimer’s disease (AD) 
at an early stage, including a Mild Cognitive Impairment (MCI) stage. Approximately 15-20% of 
people age 65 or older have MCI and approximately a third of these individuals develop a 
dementia related to Alzheimer’s disease in 5 years [1]. Amnestic MCI is defined as memory 
abnormality beyond normal age related decline with relatively intact functional capacity, in other 
words, not (yet) dementia [2].  
There continue to be no FDA approved medical therapies for MCI. In the absence of 
medical therapy, patients and families are often presented numerous recommendations regarding 
nonpharmacological interventions (e.g., start keeping notes, follow a physical exercise program, 
play computer memory games, etc.) which can be overwhelming. There is some promising 
evidence that such behavioral interventions can be beneficial in MCI. Namely, recent meta-
analyses suggest that cognitive interventions have significant, mild to moderate effect sizes 
(Hedges’ g ranging from .23 to .40) for persons with MCI (pwMCI) on multiple cognitive 
domains, including memory, attention, and processing speed [3]. Meta-analysis of non-cognitive 
effects of cognitive interventions in pwMCI demonstrated small, but significant effects for 
activities of daily living (ADLs; Cohen’s d = 0.23), mood (d = 0.16), and metacognitive 
outcomes (i.e., how one thinks/feels about one’s memory; d = 0.30) [4]. Physical exercise meta-
analysis outcomes in individuals over 50 have provided similar, moderate, overall effect sizes on 
cognition (mean effect size = .29) [5].  
Only recently have enough studies been completed on individual interventions in 
cognitive rehabilitation, physical exercise training, or psychotherapy to allow meaningful meta-
analyses like these to emerge in the literature. Still, these reviews struggle with blending an array 

of various approaches to such interventions, in different delivery systems, in differing “doses,” 
and with different measured outcomes. In other words, there still is not consensus on the best 
method to deliver a specific behavioral intervention. Nor is there a consensus regarding how to 
measure the outcomes. Yet there is increasing support for the use of multi-component 
interventions in dementia prevention efforts [6].  For example the Alzheimer’s Association is 
currently funding a $20 million study of physical exercise, diet, cognitive and social stimulation 
and improved self-management of health conditions (particularly blood pressure). Yet there is a 
dearth of literature examining the effectiveness of various behavioral interventions in 
comparison to each other.  
Previously, we have compared outcomes for a compensatory cognitive rehabilitation 
intervention and computerized cognitive exercise intervention as well as no-treatment control 
groups in randomized trials [7, 8]. In these studies, patient memory related ADLs (mADLs) were 
significantly improved over no treatment in those randomized to the cognitive rehabilitation 
condition (but not for those completing computerized cognitive exercise), and sense of memory 
self-efficacy significantly improved for those trained in use of the calendar system (but not in the 
computerized cognitive exercise or no treatment conditions) [7, 8]. Further, partners in both 
treatment groups showed stable mood and anxiety while partners in the untreated group showed 
worsening depression and anxiety over 6 months [9]. Similarly, systematic review of the 
literature has supported that various computerized interventions aimed at improving cognition 
may have impact on reducing anxiety and depression in individuals with MCI, and those trained 
with therapists in compensatory strategies (like the calendar training highlighted above) show 
more impact on ADLs, self-beliefs about memory, and confidence [4].  

There is significant debate within the field as to which outcomes to measure and how to 
consistently measure them. The vast majority of studies of behavioral interventions to date have 
focused on the impact on cognition itself for older adults or for those with MCI. However, the 
growing culture of patient centered care considers patients to be members of the healthcare team 
with an active voice in their treatment and care. There is increasing awareness of the need to ask 
what our patient want from an intervention. However, no trials to date have utilized the input of 
persons with MCI (pwMCI) or their family members in the study design and selection of 
outcomes. Thus, in the first aim of this larger study, we established that pwMCI and their 
partners rated patient quality of life (QOL), patient self-efficacy, patient mood, and memory 
dependent ADLs (mADLs) to be the more important target outcomes for behavioral 
intervention[10, 11].  
In the subsequent aims, results of which are reported here, we sought to compare the 
effectiveness of the five behavioral interventions that compose the Mayo Clinic HABIT Healthy 
Action to Benefit Independence and Thinking® Program, a 50 hour behavioral intervention 
treatment program with 5 components in impacting those highly valued outcomes by pwMCI. 
The 5 components include physical exercise, computerized brain fitness, patient and family 
education, support group, and cognitive rehabilitation with a compensatory memory support 
system (calendaring system). Each of these interventions was originally chosen on a theoretical 
basis, because each had support individually in the literature for effectiveness when compared to 
no treatment controls across a variety of outcomes [e.g., cognitive functioning, QOL, mood, 
partner burden] [4, 12] [3, 5].  
Methods 

Full details of the study protocol and recruitment have been reported previously [13], and briefly 
summarized below. 
Patient and Partner Engagement. Prior to obtaining funding we created patient/partner and 
stakeholder advisory groups. The patient/partner advisory group included 8 members, all of 
whom had completed the HABIT clinical program (described below). Each recruitment site had 
a patient or partner representative included. The stakeholder advisory group included 
representatives of the Alzheimer’s Association Chapters in Minnesota and Florida, as well as a 
representative from the Minnesota Board on Aging. Both advisory groups reviewed our 
preliminary protocol. The patient and partner advisory group strongly encouraged the conduct of 
the comparative effectiveness protocol in such a way as to ensure that all participants received 
substantial treatment; they endorsed our randomized suppression of one treatment component 
over a design involving a no treatment control. The advisory group also provided pilot data for 
Aim 1 of the study as reported elsewhere [9]. The patient and partner advisory group met the 
principal investigators via teleconference monthly during the first year of the project and roughly 
quarterly thereafter to provide feedback regarding recruitment strategies and other issues. The 
most engaged of the advisors served as co-authors of the published protocol paper [11] and were 
briefed on the final results.  
Participants 
Dyads consisting of a pwMCI and a partner participated in the interventions. 272 such 
couples were recruited through clinical services at Mayo Clinic in Minnesota, Arizona, and 
Florida as well as University of Washington. Consecutive candidates with diagnoses of amnestic 
MCI (single or multi-domain) [2] were screened and if potentially eligible approached for the 
study. They then underwent further evaluation based upon study inclusion/exclusion criteria and 

enrolled in the trial. Inclusion criteria included a Clinical Dementia Rating (CDR) [14] < 0.5, not 
taking, or stable on, nootropic medication for at least 3 months, fluent in English, and able to 
attend with a cognitively normal (Mini Mental Status Exam [15] >24) care partner who had at 
least twice-weekly contact with the pwMCI. Exclusion criteria included current participation in 
another treatment-related clinical trial or significant auditory, visual, or motor impairment 
impacting ability to participate in the program. PwMCI completed the Dementia Rating Scale-2 
[14] as a measure of general cognitive function at baseline. 
Intervention and Randomization: 
The intervention lasted 10 days over the course of two weeks. Briefly, for group 
assignment, we utilized a subtraction model, randomizing groups of couples to have one of the 
five potential interventions withheld while receiving the other four. Block randomization was 
utilized to suppress one of the five components from groups of 10-20 couples in each session. 
Resulting randomization and allocation to each group per site can be viewed in Table 2. Each of 
the 4 study sites ran at least 5 sessions to allow for suppression of each component at least once 
at each site. In order to achieve our enrollment goals, each Mayo Clinic site ran an extra session.  
Components of HABIT include: 
1. Yoga: Participants engaged in daily 45-60 minute sessions of yoga for physical exercise 
and relaxation training with certified yoga instructors. They were provided a customized 
DVD to encourage continued practice post-HABIT [16]. 
2. Brain fitness: Participants completed 45-60 minute sessions of cognitive training daily 
via the commercially available BrainHQ product available from Posit Science 
Corporation. They were provided a one year subscription to the program to encourage 
continued use post-HABIT. 

3. Wellness education: Couples attended daily 45-50 minute lectures covering a range of 
health topics such as Living with MCI, Changes in Roles and Relationships, Sleep 
Hygiene, MCI and Depression, Nutrition, and Assistive Technology. Couples were given 
resources and written information to inform their choices towards incorporating the 
healthy behavioral changes discussed in the lectures (e.g., improving diet) into their lives 
post-HABIT. 
4. Support groups: The pwMCI and partners met separately in support groups for 45-60 
minutes each day. The pwMCI support group focused on reminiscence-focused group 
sessions with the opportunity for discussion of MCI related concerns as desired by the 
participants. The partner group was a traditional support group facilitated by a therapist 
around caregiving themes. 
5. Cognitive rehabilitation: The pwMCI received cognitive rehabilitation daily focused on 
compensatory-focused memory support system (MSS) development (i.e., a calendar/note 
taking system). This involved training from a structured curriculum in use of a two page 
per day written memory book to develop compensatory written reminders for important 
appointments, tasks, or experiences/thoughts of the day. Both pwMCI and partners were 
provided the paper MSS materials in an ongoing manner to enable continued use of the 
system post-HABIT. 
Outcome Measures:  
Completed by the pwMCI:  
Participant QOL was the primary outcome measure as assessed by the Quality of Life-AD 
(QOL-AD)[17] overall score. Participant mood was measured by the Center for Epidemiological 

Studies Depression scale (CES-D)[18], and participant self-efficacy was assessed using 
modified, selected items from the Chronic Disease Self-Efficacy Scales[19].  
Completed by the Partner: 
Patient memory functional status: Participant functional memory was assessed by 8 memory-
related items on the informant-based Everyday Cognition (E-Cog)[20] questionnaire.  
Timing. 
All measures were completed at baseline, treatment end, 6 months, and 12 months post 
intervention. Six-months and 12 month data collection was part of a one-day booster session that 
included a refresher for each of the 4 interventions originally provided [13]. 
Adherence. 
Adherence to taught program activities as well as possible treatment diffusion of the 
withheld intervention were assessed at 6 and 12 months post intervention by asking pwMCI and 
their program partners to log how much time spent in each of the 5 intervention related activities. 
We categorized participants into three levels of adherent: adherent, non-adherent, or 
indeterminate. Table 1 displays how each level of adherence was defined for each of the 5 
interventions and references the standard in the literature to support each definition of adherent. 
Power analysis. 
We used approaches developed for this design to estimate the power to conclude that a 
specific HABIT® component provided benefit on the primary outcome. Data from a prior 
clinical sample and a matched, non-randomized, untreated control group provided initial 
estimates for this power estimation. We computed the expected variance of the estimated 
treatment effect for one HABIT® component by extracting the appropriate value from the 
variance-covariance matrix derived from the design matrix corresponding to the allocation of 

treatment groups within the study. Using this, we estimated the magnitude of the effect size 
(difference score divided by its standard deviation) that is detectable with 80% power using a 
two-sided 0.05 level test. The results of this effort suggest that we had approximately 80% power 
to conclude that a treatment component is efficacious if it is associated with an improvement of 
0.53 standard deviation units (d = 0.53) while accounting for effects due to the other treatment 
components, study sites, and sessions within sites. We have observed differences larger than this 
in previous studies. For instance, we observed that training in the MSS improves E-cog scores by 
nearly 0.9 standard deviations at first follow-up in a previous study [8]. Therefore the study had 
sufficient power to detect meaningful changes of magnitudes that we expected.  
Statistical analysis. 
For analysis of the primary aim, we utilized linear mixed-effects regression models to 
obtain the estimated change in each of the four outcome measures (QOL, self-efficacy, mood, 
and functional ability) from baseline to 12 months along with 95% confidence intervals (CIs) for 
the 5 separate study arms. The model included the outcome measure at 4 time points (baseline, 
end of treatment (EOT), 6-month follow-up, and 12-month follow-up) with separate random 
effects for participant, session, and time point within session. Fixed effects included indicator 
variables for each of the 4 sites, age, sex, interactions of age and sex with each of the 3 non-
baseline time points (6 parameters), and indicator variables representing each of the 5 treatments 
at each of the 3 non-baseline time points (15 parameters). We reported the coefficients 
corresponding to each of the study arms at 12 months along with the 95% profile confidence 
intervals and likelihood ratio test p values in addition to the coefficients corresponding to each of 
the study arms at EOT and 6 month follow-up. The coefficients were reported as the fitted mean 
change in outcome from baseline to the given time point for an individual with covariates equal 

to their mean values. In addition, we performed likelihood ratio tests to evaluate whether there 
was evidence of differences in outcome between study arms at EOT, 6 months, and 12 months. 
Additional sensitivity analyses were performed. Analyses were performed using R statistical 
software (version 3.2.3, R Foundation for Statistical Computing, Vienna, Austria). 
Results 
Participants 
There were 272 participants from 4 sites who were randomized as described above to one 
of five study arms after enrollment (Figure 1). Participant baseline characteristics are described 
in Table 2 according to study arm. There were no meaningful differences in demographics or 
general cognitive status across sites or samples.  Participants in the no support group arm were 
slightly more likely to be taking memory medications.  Two hundred eleven of these participants 
completed the study.  Two participants died over the course of follow-up, 42 participants 
formally withdrew (predominantly due to health concerns of participant or partner, or because of 
time commitments) and 17 participants were lost to follow-up.   
Outcome Measures 
Results by suppression group for QOL, mADLs, mood, and self-efficacy are displayed in 
Table 3. 
Quality of Life 
All 5 study arms showed improvement in QOL-AD overall score from baseline to EOT 
with the fitted mean change from baseline ranging from 1.10 (no support groups) to 1.55 (no 
wellness education) (all p ≤ 0.049), but these changes were not sustained through 6-month or 12-
month follow-up. There was no evidence of a difference between study arms in change in QOL-
AD from baseline at EOT (p=0.98), 6-month follow-up (p=0.38), or 12-month follow-up 

(p=0.21). In comparative effectiveness analysis at 12 months, and in the context of treatment 
which also includes MSS, support groups, and yoga, replacing BF with wellness education 
appeared to have significant positive impact on QOL (effect size = 0.34, p = .02). See Figure 2a. 
Self-efficacy 
At EOT there were improvements in self-efficacy from baseline for the arm with no 
support group, no MSS training, and no yoga. At 6 months, the arm with no yoga had 
statistically significant worsening of self-efficacy, though there were no significant within group 
changes by 12 months. There were no statistically significant differences between study arms in 
change in self-efficacy from baseline at EOT (p=0.58), 6-month follow-up (p=0.19), or 12-
month follow-up (p=0.23). In comparative effectiveness analysis at 12 months, and in the context 
of treatment which also includes MSS, wellness, and yoga, replacing BF with support group had 
a significant positive impact on self-efficacy (effect size = 0.31, p = .04. See Figure 2b. 
Mood 
Three of the five arms (no MSS, no BF, and no yoga) showed an improvement in mood 
from baseline to EOT. The remaining two arms showed change in the direction of improvement, 
but were not statistically significant. At 6-month follow-up there was no evidence of a change 
from baseline for any of the 5 arms. At 12-month follow-up the arm with no BF training showed 
an improvement in mood, while the arm with no wellness education showed a significant 
worsening in mood. A likelihood ratio test detected overall differences between the 5 study arms 
in change in mood from baseline to 12-months and the confidence intervals in Table 3 suggest 
these differences are between the arm with no wellness education (mean fitted change 95% CI: 
0.50 to 4.33) and no computerized brain fitness training (mean fitted change 95% CI: -3.79 to 
0.00). In the context of multicomponent treatment involving four interventions, replacing BF 

with another intervention appeared to have significant positive impact on mood as follows: 
replace with wellness education (effect size = 0.53, p = .001), replace with yoga (effect size = 
0.34, p = .035), and replace with MSS calendar training (effect size = 0.34, p = .04). These 
findings suggest only support groups were not statistically better than BF in terms of impact on 
patient mood. See Figure 2c. 
Functional Memory Ability 
The study arm with no support group was the only group to have a significant 
improvement in everyday memory from baseline to EOT. There was no evidence of change in 
any group for everyday memory from baseline to 6-month follow-up. By 12-month follow-up, 
all of the groups had a significant worsening of everyday memory function with the exception of 
the arm with no support groups. There were no statistically significant differences between study 
arms in change in everyday cognition from baseline at EOT (p=0.10), 6-month follow-up 
(p=0.90), or 12-month follow-up (p=0.07). See Figure 2d. 
Impact of Ongoing Adherence 
Adherence at 12 months to the various components had minimal impact on QOL or mood 
outcomes. Adherence to exercise broadly was positively associated with self-efficacy outcomes 
(p < .05, d = .29) and mADLs outcomes (p < .05, d = .26). Wellness adherence was positively 
associated with mADL outcomes as well (p < .05, d = .22). Adherence impact on outcome 
variables is presented in Table 4. 
Discussion 
In 2017, the National Academies of Sciences Engineering and Medicine (NAS) released 
its report evaluating strategies aimed at preventing or delaying normal age related cognitive 
decline, MCI, or Alzheimer’s-type dementia[21]. That report concludes that the data do not 

currently support a widespread public health campaign for any particular prevention strategy. 
However, they report promising results with one medical intervention (blood pressure 
management) and two behavioral interventions: cognitive training and physical activity. In this 
study, we sought to examine the comparative effectiveness of behavioral interventions, including 
cognitive training through either the MSS compensation system or computerized BF training and 
physical activity through yoga, as well as the impact of wellness education and supportive group 
therapy on individuals with MCI.   
This study was a patient-centered comparative effectiveness outcome study. Thus, our 
methodology and results were guided by former behavioral intervention program participants 
and patient/partner focus groups (see full protocol[13]). As a consequence, the primary outcomes 
were defined by our former patients as QOL, self-efficacy, mood, and mADLs[11]. Further, we 
were prompted to forgo the traditional “additive” approach of clinical trials of randomly adding 
participants to one intervention at a time, to undertake a novel, “subtractive” approach of 
randomly withholding one intervention at a time. This assured that all participants would receive 
substantial interventions while still permitting comparison of the components. This design 
inverts the typical interpretation of intervention studies. Rather than looking to associate the best 
outcomes with the presence of an intervention, this design requires consideration which groups 
has the poorest outcomes associated with a missing intervention.  
Treatment End 
Immediately after the intervention, all combinations of behavioral intervention resulted in 
reports of improved QOL. Thus, each of our interventions actually may positively impact QOL 
in the short run. It could be argued that simply participating in an intensive group intervention 
leads to a sense of better QOL immediately following the group, regardless of what the 

intervention is, simply because the act of doing something rather than nothing fosters an 
improved sense of QOL. On the other hand, meta-analysis of cognitive interventions in MCI 
have not previously been shown to significantly impact on QOL[4], suggesting mere contact 
alone may not produce improved QOL.  
All groups except those missing BF showed statistically significant improvements in self-
efficacy by treatment end. This suggests that not participating in BF may have some cost in 
terms of improved self-efficacy. The findings regarding self-efficacy are in keeping with an 
overall positive effect size of d = .30 for meta-cognitive variables such as sense of self-efficacy 
reported in a prior meta-analysis of cognitive interventions for MCI[4]. However, our finding 
stands in contrast to prior studies showing computerized training interventions did not impact 
beliefs about one’s memory ability confidence [22, 23].  
Mood improved significantly by treatment end for the no MSS, no BF, and no yoga 
groups, but did not improve for the no support group or no wellness education groups. Thus, 
support group and wellness education may be more important in mood improvement than MSS, 
BF, or yoga at treatment end. Improvement in mADLs at treatment end was only observed for 
those not receiving support group. Thus, support group did not appear to play a significant role in 
improving mADLs in the near term or conversely, the combination of MSS, BF, yoga and 
wellness was most potent at improving near term mADLs. 
12 Month Follow-Up 
We were particularly interested in the lasting effects of these interventions over time, 
after the initial “honeymoon” period of participation subsided. By 12 months post intervention, 
the group that did not have computerized BF training had the best reported QOL whereas the 
group that did not receive wellness education had the lowest QOL and was the only group with 

worsening QOL relative to baseline. This would suggest that in terms of QOL there was no cost 
to withholding BF but that there was significant cost to QOL for withholding wellness education. 
More specifically, a combination of MSS training, support group, wellness education, and yoga 
had the best outcomes on QOL and replacing wellness with brain fitness elevated that benefit. 
The 12-month outcomes for mood followed a similar pattern as QOL with the exception that the 
benefits of retaining yoga and MSS over brain fitness were also statistically supported.  
The group that did not have computerized brain fitness training also showed the best 
improvement of the groups at 12 months post intervention in self-efficacy. As such, the 
combination of MSS training, support group, wellness education, and yoga may have the best 
outcomes for self-efficacy. The group that did not receive support group had a decline in self-
efficacy suggesting that support group may be a key component to positively impact self-
efficacy.  
Previous work suggests that those who adhere better to the interventions of a study in the 
long run also are likely to have better outcomes [8, 24]. In this study, adherence to exercise 
broadly improved self-efficacy, and adherence to exercise and wellness improved mADLs. There 
is much still to be determined about the impact on adherence to outcomes. For example, of the 
interventions, the physical exercise component (broadly defined) had the most individuals still 
adherent at one year (55%) compared to the other variables (BF = 25%, wellness = 23%, MSS = 
12%, and support group 9%), giving more power to detect significant differences in the physical 
exercise component for adherent and non-adherent groups. Further, our grading of adherence is 
not equivalent across interventions. For example we required strict use to our particular calendar 
and brain fitness programs to be considered adherent to those components but accepted any form 
of physical exercise towards adherence to the physical exercise component. This makes it 

difficult to compare impact of adherence across components in this study design.  Most 
behavioral interventions in this area are intended not as one time treatments, like a course of 
antibiotics but more as life-style modifications intended to persist as long as possible.  Research 
on efficacious and cost-effective ways to optimize adherence is needed.  
In this type of behavioral intervention treatment diffusion is also a problem. In drug trials 
it is generally difficult to get the experimental medication unless your are randomized to it.  But 
here participants could freely engage in the behaviors that had been suppressed in their 
intervention arm. For example, 82% of the physical exercise suppressed group met physical 
exercise adherence guidelines at 10 months, which is nominally higher that the overall average. 
After intervention, reported participation in support groups was equally likely in the no support 
group arm as any other arm.  No one would wish for participants to avoid activities that could 
benefit them but this does produce confounds perhaps unique to behavioral research that can 
diminish the ability to detect treatment differences.  
We should expect that the comparative effectiveness of different behavioral interventions 
for MCI is dependent upon the specific outcome targeted. Unsurprisingly, the interventions a 
pwMCI should pursue likely depend on which outcomes are most important to the individual. 
We acknowledge that in this study, interpretation of the impact of NOT getting an intervention 
component was counter to the design of most clinical trials who report the impact of receiving an 
intervention. However, maximizing the number of interventions received was of great import to 
our patient advisors in designing this trial [13]. To try to help simplify the explanation of the 
results, we also sought to statistically examine the impact of receiving each component by 
comparing each intervention to the intervention found to have the minimal overall impact: brain 
fitness. When viewed in this manner, wellness education appears to be most important to QOL at 

one year post intervention; wellness education, yoga, and MSS calendar training were important 
for mood outcomes; support group had a positive impact on self-efficacy, and yoga was most 
beneficial to mADLs. Thus, for participants who share the same opinions as our former HABIT 
alumni in choosing outcomes of most importance (patient QOL, self-efficacy, mood, and 
functional ability[11], the most benefit would be found in the long term of participating in a 
program that included wellness education, yoga, MSS calendar training, and support group. The 
same alumni group also ranked the importance of our interventions overall as 1) MSS, 2) support 
group, 3) wellness education, 4) yoga, and 5) brain fitness [11], further supporting the 
importance of these top four interventions.  Though these findings are preliminary, they provide 
a start on the development of ‘personalized’ intervention protocols wherein the interventions are 
tailored to the outcomes of greatest importance to the pwMCI and his or her support network. 
Other outcomes including pwMCI cognition, time to dementia diagnosis and partner QOL, mood 
and burden, are available to us as secondary outcomes and will be reported elsewhere.  
For the time being however, the urgency of dementia and an individual and public health 
concern is great[21]. Under the circumstances it is reasonable to pursue all possible behavioral 
approaches in multiple components programs as studied here and deployed in the World Wide 
Fingers network (wwfingers.com).  
While we utilized our particular version of these interventions, similar behavioral 
interventions (therapy based cognitive rehabilitation, computerized brain training programs, 
physical exercise, psychotherapy/group therapy, and education programs for memory loss) are 
being offered in various combinations in medical and research centers around the world[4]. 
While our exact conclusions may not generalize to other forms of the behavioral intervention 
(e.g., resistance training as physical exercise versus yoga), we offer these results as a starting 

point in the literature to begin these sorts of comparative effectiveness trials. Future research thus 
can look at the nuances of different types of physical exercise compared to different types of 
therapist based cognitive rehabilitation, etc., and combinations thereof.  The recruited cohort was 
ultimately not diverse and was highly educated.  It is not clear how results might change in more 
representative samples or in specific underrepresented populations.   
 
Conclusions:  Wellness education had the most impact on our highest patient ranked outcome of 
QOL by one year post intervention. Psychological outcomes of mood and self-efficacy were 
most positively impacted at one year by participating in a combination of wellness education, 
yoga, compensation based calendar training (the MSS) and supportive group therapy. When 
functional independence was considered as the outcome, a combination of MSS training, 
computer BF, wellness education, and yoga appeared to be of most benefit in maintenance of 
mADLS, with particular decline if yoga was not included. 
 
 
 

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Table 1. Classifications of Adherence at 12 month Follow-Up 
 
Adherent 
Non-Adherent 
MSS Calendar 
Compliance score > 7[25] 
Less than daily 
Computerized BF 
40 hours post program (2 hours 
per week for 6 months)[24] 
Less than 1 hour per week 
Physical Activity 
150 minutes a week[26] 
Less than 60 minutes per week 
Supportive Therapy 
Activity Log participating in 
individual or group therapy 
“Not at all” 
Wellness Education 
Activity Log answer of “once, 
twice or more than twice in 
past 2 weeks” 
“Not at all” 
Note. MSS = Memory Support System, BF = Brain Fitness. Rationale for the cut-off adherence 
standard is referenced as applicable. Non-adherent fell far lower than those standards. All 
responses not falling into the adherent or non-adherent categories were labeled as 
“indeterminate.”   
 
 

 
Table 2: Participant baseline characteristics by study arm 
Table 1 Participant baseline characteristics by study arm 
 
 
No Brain Fitne
ss 
(N=54) 
No MSS 
(N=57) 
No Support Grou
p 
(N=53) 
No Wellness 
(N=52) 
No Yoga 
(N=56) 
p value 
Age 
  
  
  
  
  
0.642 
    N 
54 
57 
53 
52 
56 
  
    Mean (SD) 
75.8 (8.0) 
74.3 (8.1) 
75.1 (7.3) 
76.5 (7.2) 
74.3 (7.3) 
  
    Median 
75.0 
75.0 
75.0 
76.0 
74.5 
  
    Q1, Q3 
71.0, 82.0 
69.0, 80.0 
71.0, 80.0 
72.0, 80.0 
70.0, 80.5 
  
    Range 
(53.0-95.0) 
(56.0-91.0) 
(57.0-88.0) 
(59.0-94.0) (58.0-87.0) 
  
Gender 
  
  
  
  
  
0.951 
    Male 
33 (61.1%) 
31 (54.4%) 
32 (60.4%) 
30 (57.7%) 34 (60.7%) 
  
    Female 
21 (38.9%) 
26 (45.6%) 
21 (39.6%) 
22 (42.3%) 22 (39.3%) 
  
Years of education 
  
  
  
  
  
0.37 
    N 
53 
57 
53 
52 
56 
  
    Mean (SD) 
16.0 (2.7) 
15.8 (3.0) 
16.1 (3.0) 
15.8 (2.6) 
16.6 (2.8) 
  
    Median 
16.0 
16.0 
16.0 
16.0 
16.5 
  
    Q1, Q3 
14.0, 18.0 
14.0, 18.0 
14.0, 19.0 
14.0, 18.0 
16.0, 19.0 
  
    Range 
(12.0-20.0) 
(6.0-20.0) 
(10.0-20.0) 
(12.0-20.0) 
(9.0-20.0) 
  
Race,  
  
  
  
  
  
0.361 
   Non-white 
1 (1.9%) 
5 (8.8%) 
2 (3.8%) 
1 (1.9%) 
3 (5.4%) 
  
    White, non-hispanic 
53 (98.1%) 
52 (91.2%) 
51 (96.2%) 
51 (98.1%) 53 (94.6%) 
  
DRS Total Raw Score 
  
  
  
  
  
0.252 
    N 
54 
55 
53 
51 
49 
  
    Mean (SD) 
127.5 (9.3) 
129.7 (8.8) 
130.9 (7.6) 
128.2 (8.0) 127.7 (18.7) 
  
    Median 
129.5 
132.0 
132.0 
129.0 
131.0 
  
    Q1, Q3 
122.0, 135.0 
124.0, 136.0 
127.0, 136.0 
122.0, 135.0 124.0, 138.
0 
  
    Range 
(97.0-142.0) 
(100.0-
143.0) 
(110.0-141.0) 
(108.0-
141.0) 
(14.0-
143.0) 
  
Partner  
  
  
  
  
  
0.131 
    Missing 
0 
4 
0 
0 
0 
  
    Adult Child, sibling, 
other 
10 (18.5%) 
12 (22.6%) 
5 (9.4%) 
8 (15.4%) 
4 (7.1%) 
  
    Spouse 
44 (81.5%) 
41 (77.4%) 
48 (90.6%) 
44 (84.6%) 52 (92.9%) 
  

Table 1 Participant baseline characteristics by study arm 
 
 
No Brain Fitne
ss 
(N=54) 
No MSS 
(N=57) 
No Support Grou
p 
(N=53) 
No Wellness 
(N=52) 
No Yoga 
(N=56) 
p value 
Current memory 
medications 
  
  
  
  
  
0.021 
    Missing 
0 
4 
0 
3 
1 
  
    No 
30 (55.6%) 
31 (58.5%) 
42 (79.2%) 
33 (67.3%) 28 (50.9%) 
  
    Yes 
24 (44.4%) 
22 (41.5%) 
11 (20.8%) 
16 (32.7%) 27 (49.1%) 
  
(report generated on 20JUL2018) 
1Chi-Square    2Kruskal Wallis 
 
 
 

 
Table 3: Fitted mean change from baseline in QOL, mADL, mood, and self-efficacy. 
 
Outcome 
Study Arm  
Change BL to EOT 
(95% CI) 
Change BL to 6 
months (95% CI) 
Change BL to 12 
months (95% CI) 
QOL 
No Wellness  
1.55 (0.40, 2.69)** 
0.55 (-0.64, 1.72) 
-0.85 (-2.06, 0.33) 
 
No MSS  
1.31 (0.22, 2.41)* 
0.22 (-1.02, 1.49) 
-0.01 (-1.19, 1.19) 
 
No Support  
1.10 (0.01, 2.25)* 
0.47 (-0.71, 1.67) 
0.36 (-0.82, 1.59) 
 
No Yoga 
1.52 (0.45, 2.57)** 
-0.84 (-1.95, 0.28) 
0.61 (-0.53, 1.73) 
 
No Computer  1.33 (0.24, 2.43)* 
0.51 (-0.65, 1.67) 
1.07 (-0.11, 2.26)┼  
mADL 
No Wellness  
-0.36 (-1.38, 0.67) 
0.38 (-0.68, 1.44) 
1.15 (0.08, 2.22)* 
 
No MSS  
0.48 (-0.50, 1.45) 
0.47 (-0.66, 1.59) 
1.29 (0.24, 2.35)* 
 
No Support  
-1.34 (-2.32, -0.37)** 
0.21 (-0.86, 1.29) 
0.42 (-0.66, 1.49) 
 
No Yoga 
-0.35 (-1.30, 0.59) 
0.36 (-0.64, 1.35) 
2.52 (1.52, 3.53)*** 
 
No Computer  0.09 (-0.88, 1.06) 
0.91 (-0.12, 1.94) ┼ 1.09 (0.03, 2.14)* 
Mood 
No Wellness  
-1.75 (-3.58, 0.08)┼ 
1.22 (-0.66, 3.10) 
2.42 (0.50, 4.33)** 
 
No MSS  
-3.68 (-5.44, -1.93)*** 
-0.52 (-2.52, 1.47) 
0.87 (-1.03, 2.76) 
 
No Support  
-1.02 (-2.76, 0.72) 
-0.54 (-2.45, 1.36) 
-1.00 (-2.94, 0.93) 
 
No Yoga 
-2.47 (-4.17, -0.77)** 
0.34 (-1.46, 2.13) 
0.86 (-0.96, 2.68) 
 
No Computer  -3.47 (-5.21, -1.72)*** 
-1.62 (-3.48, 0.25) 
-1.90 (-3.79, 0.00)* 
SE 
No Wellness  
2.79 (-0.12, 5.69)┼ 
0.47 (-2.51, 3.46) 
-0.74 (-3.78, 2.30) 
 
No MSS  
4.83 (2.05, 7.62)*** 
1.66 (-1.54, 4.85) 
1.09 (-1.92, 4.10) 
 
No Support  
4.91 (2.14, 7.69)*** 
1.4 (-1.61, 4.42) 
-2.48 (-5.52, 0.56) 
 
No Yoga 
3.66 (0.97, 6.36)** 
-2.86 (-5.70, -
0.02)* 
-1.82 (-4.70, 1.05) 

 
No Computer  
2.26 (-0.52, 5.04) 
-0.23 (-3.19, 2.73) 
1.82 (-1.18, 4.83) 
Note. BL = baseline; EOT = end of treatment; MSS = Memory Support System; QOL = Quality 
of Life; mADL = memory related activities of daily living; SE = self-efficacy. A positive change 
from baseline indicates and improvement in quality of life and self-efficacy. A negative change 
from baseline indicates and improvement in mADL and mood. Fitted mean change from baseline 
to each of the three time points was estimated from a linear mixed-effects regression model (see 
statistical analysis section for details) for a hypothetical average participant.  
* =  p < .05, ** p < .01, *** = p < .001, ┼ = p = .06 to .08 
 
 

Comparing Behavioral Interventions      29 
 
 
Table 4. Impact of Adherence by 12 month Follow Up on Outcomes 
 
Adherence to 
QOL 
Mood 
Self-Efficacy 
mADLs 
Wellness 
0.12 
(-0.10,0.33) 
-0.01  
(-0.25, 0.23) 
-0.05 
(-0.27, 0.18) 
0.22*  
(0.00, 0.45) 
MSS 
0.00 
(-0.28, 0.27) 
0.05  
(-0.25, 0.36) 
0.16 
(-0.12, 0.44) 
0.08  
(-0.20, 0.35) 
Support 
0.06 
(-0.24, 0.37) 
-0.27  
(-0.61, 0.07) 
0.22 
(-0.09, 0.53) 
-0.30  
(-0.62, 0.01) 
Yoga/Exercise 
0.10 
(-0.09, 0.29) 
0.07  
(-0.14, 0.28) 
0.29* 
(0.09, 0.49) 
0.26*  
(0.05, 0.46) 
Computerized 
Brain Fitness 
0.00 
(-0.21, 0.21) 
0.01  
(-0.22, 0.25) 
0.02 
(-0.20, 0.23) 
0.14  
(-0.07, 0.36) 
Note. QOL = Quality of Life; mADLS – Memory Related Activities of Daily Living; MSS = 
Memory Support System. 
Adherence is defined here as: adherent at both 6 and 12 months (considered non-adherent if 
indeterminate or missing at 6 or 12 months). Estimates and 95% confidence intervals for the 
change in outcome scores from baseline to 12 months are given as standardized effect sizes. 
Estimates result from linear mixed effects models with stratification by adherence at 6 and 12 
months to the given HABIT intervention. * =  p < .0 
 
 

Comparing Behavioral Interventions      30 
 
Figure 1. 
 
 
 

Comparing Behavioral Interventions      31 
 
Figure 2 
a. 
 
b. 
 
 
 
c.  

Comparing Behavioral Interventions      32 
 
 
d.