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In the United States, more than 6 million adults live with Alzheimer disease (AD) that affects 1 out of every 3 older adults. Although there is no cure for AD currently, lifestyle-based interventions aimed at slowing the rate of cognitive decline or delaying the onset of AD have shown promising results. However, most studies primarily focus on older adults (>55 years) and use in-person interventions.
The aim of this study is to determine the effects of a 2-year digital lifestyle intervention on AD risk among at-risk middle-aged and older adults (45-75 years) compared with a health education control.
The lifestyle intervention consists of a digitally delivered, personalized health coaching program that directly targets the modifiable risk factors for AD. The primary outcome measure is AD risk as determined by the Australian National University-Alzheimer Disease Risk Index; secondary outcome measures are functional fitness, blood biomarkers (inflammation, glucose, cholesterol, and triglycerides), and cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status and Neurotrack Cognitive Battery). Screening commenced in January 2021 and was completed in June 2021.
Baseline characteristics indicate no difference between the intervention and control groups for AD risk (mean −1.68, SD 7.31;
The intervention in the Digital, Cognitive, Multi-domain Alzheimer Risk Velocity is uniquely designed to reduce the risk of AD through a web-based health coaching experience that addresses the modifiable lifestyle-based risk factors.
ClinicalTrials.gov NCT04559789; https://clinicaltrials.gov/show/NCT04559789
DERR1-10.2196/31841
Alzheimer disease (AD) is a chronic neurodegenerative disorder characterized by the buildup of neurofibrillary tangles and plaques in the brain and a steady decline in memory and executive function. These cognitive changes eventually lead to physical dependence [
In addition to being a significant contributor to deaths among US adults, AD is a major burden to the health care system. AD accounts for an estimated US $355 billion in annual direct and indirect health care costs [
AD is a multifactorial disease that involves several mechanisms that contribute to its development and progression. Nonmodifiable risk factors include advanced age, female sex, and presence of the apolipoprotein E4 (APOE4) allele. Such nonmodifiable risk factors are important to consider when assessing an individual’s risk for developing AD, but nothing can be done to address these factors. However, some modifiable risk factors (eg, lipids, glucose, inflammatory factors, and multiple lifestyle behaviors) have been identified as possible contributors to the disease [
Many modifiable risk factors for vascular disease are known to concurrently contribute to the development of AD [
The average age of AD diagnosis is 75.5 (SD 9.7) years [
Several studies have investigated single-domain lifestyle interventions to lower the risk of dementia and AD [
Owing to the limited efficacy of the single-domain interventions, researchers have begun to investigate the use of multi-domain lifestyle interventions that target various factors associated with cognitive decline [
Although these results are promising, not all multi-domain interventions have resulted in cognitive improvements. For instance, prevention of dementia by intensive vascular care [
Of the studies on multi-domain lifestyle interventions for reducing AD risk, few have tested middle-aged individuals and few have implemented digital interventions. Using the intervention program earlier in the disease course can maximize its benefits, and using digital technologies rather than relying on face-to-face implementation can greatly increase the reach and scalability of these programs. Therefore, the purpose of the DCMARVel trial is to determine the effects of a 2-year digital, multi-domain lifestyle intervention on AD risk among at-risk middle-aged to older adults (45-75 years). Moreover, the digital and personalized nature of the intervention provides the opportunity to explore the variables that may contribute to the accessibility and subsequent adherence to an AD risk reduction intervention. This paper outlines the study protocol and baseline characteristics of the study population. The main aims of this study are as follows: (1) to determine the effect of a 2-year digital, multi-domain AD risk reduction intervention on the overall risk of AD in adults at risk of developing the disease; (2) to determine the effect of digital interventions on the rate of cognitive decline; and (3) to determine the effect of digital interventions on the changes in general health outcomes.
This is a single-site, 2-year randomized controlled trial (RCT). The participants include men and women aged from 45 to 75 years who have risk factors for dementia. Each participant has been informed of the purpose of the intervention and has agreed to be assigned randomly into 1 of the 2 study groups (HC or HE).
To be included in the study, the participants must have at least 2 positive risk factors for AD as determined by the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI) [
Age: 45-75 years
BMI: 18.5-39.9 kg/m2
Fluent in English (written and spoken)
At least 2 of the following risk factors for Alzheimer disease (AD) from Australian National University-Alzheimer Disease Risk Index (ANU-ADRI):
High school education or less
Overweight or class I or class II obese (BMI 25-39.9 kg/m2)
History of diabetes, hypertension, high cholesterol, smoking, or traumatic brain injury
At most, 1 of the following protective factors for AD from ANU-ADRI:
High level of physical activity (as defined by the high International Physical Activity Questionnaire category)
High fish consumption (as defined by consumption of fish or seafood that is not fried, for >5-6 times per week)
High level of cognitive engagement (as defined by engaging in at least 6 of the following activities several times a week: reading a book, newspaper, or magazine; playing brain games; playing games; writing letters or emails; participating in web-based social network activities; attending a concert, play, or musical; or visiting a library)
Ability to send and receive SMS text messages
Own a smartphone with a reliable internet connection and willing to use email
Ability to participate in light to moderate physical activity
Willing to be randomized
Physician diagnosis of the following:
Mental health condition (eg, eating disorder, alcohol and substance use, and schizophrenia)
Neurologic conditions (eg, epilepsy, stroke, multiple sclerosis, Parkinson disease, brain tumor, or severe traumatic brain injury)
Dementia, probable dementia, or mild cognitive impairment
Other significant health condition (eg, congestive heart failure, chronic obstructive pulmonary disease, coronary artery disease, renal failure, chronic kidney disease, and pulmonary hypertension)
Recent cardiovascular event or recent treatment for cancer (within the last year), on dialysis, or on active organ transplant list
Visual problems that prevent viewing screen at a normal distance (eg, legal blindness, detached retina, and occlusive cataracts)
History of learning disability
Currently participating in a formal cognitive training coaching program or other lifestyle change program (eg, diabetes prevention program)
Currently pregnant or planning to become pregnant in the next 2 years
Not meeting all the inclusion criteria
During the first visit, after eligibility was confirmed and informed consent was obtained, the participants completed a baseline survey. The survey contained questions about demographics (age, race or ethnicity, and education level), contact information, sleep, stress, anxiety, depression, general well-being, and dementia risk. Then, the participants completed a set of cognitive assessments, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [
Summary of measures collected at each study visit.
Category and measurement | Baseline | 4 months | 12 months | 24 months | |||||
Informed consent | Yesa | Nob | No | No | |||||
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Age (years) | Yes | No | No | No | ||||
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Race | Yes | No | No | No | ||||
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Education level | Yes | No | No | No | ||||
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Marital status | Yes | No | No | No | ||||
Resting blood pressure (heart rate) | Yes | Yes | Yes | Yes | |||||
Supplement and medication list | Yes | Yes | Yes | Yes | |||||
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Height and weight; BMI | Yes | Yes | Yes | Yes | ||||
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Body fat (DXAc) | Yes | Yes | Yes | Yes | ||||
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Lipids (LDLd, HDLe, TCf, and triglycerides) | Yes | Yes | Yes | Yes | ||||
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Glucose | Yes | Yes | Yes | Yes | ||||
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BDNFg | Yes | Yes | Yes | Yes | ||||
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hs-CRPh | Yes | Yes | Yes | Yes | ||||
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IL-6i | Yes | Yes | Yes | Yes | ||||
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Smoking and drinking habits | Yes | Yes | Yes | Yes | ||||
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Exercise and dietary patterns | Yes | Yes | Yes | Yes | ||||
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History of diabetes, depression, high cholesterol, and TBIk | Yes | Yes | Yes | Yes | ||||
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Social engagement and cognitive activity | Yes | Yes | Yes | Yes | ||||
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Fish intake | Yes | Yes | Yes | Yes | ||||
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Pesticide exposure | Yes | Yes | Yes | Yes | ||||
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Immediate memory | Yes | Yes | Yes | Yes | ||||
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Delayed memory | Yes | Yes | Yes | Yes | ||||
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Visuospatial and constructional abilities | Yes | Yes | Yes | Yes | ||||
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Language | Yes | Yes | Yes | Yes | ||||
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Attention | Yes | Yes | Yes | Yes | ||||
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Image pairs | Yes | Yes | Yes | Yes | ||||
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Symbol match | Yes | Yes | Yes | Yes | ||||
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Item price | Yes | Yes | Yes | Yes | ||||
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Arrow match | Yes | Yes | Yes | Yes | ||||
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Light reaction | Yes | Yes | Yes | Yes | ||||
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Path points | Yes | Yes | Yes | Yes | ||||
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Digital choice anxiety survey | Yes | Yes | Yes | Yes | ||||
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SPPBm | Yes | Yes | Yes | Yes | ||||
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6MWTn | Yes | Yes | Yes | Yes | ||||
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Dual-task | Yes | Yes | Yes | Yes | ||||
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Hand grip | Yes | Yes | Yes | Yes | ||||
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TENDO sit-to-stand | Yes | Yes | Yes | Yes | ||||
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Everyday Cognition (E-Cog-12o) | Yes | Yes | Yes | Yes | ||||
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Sleep (PSQIp) | Yes | Yes | Yes | Yes | ||||
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Stress (PSSq) | Yes | Yes | Yes | Yes | ||||
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Well-being (SF-12r) | Yes | Yes | Yes | Yes | ||||
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Loneliness (UCLAs) | Yes | Yes | Yes | Yes | ||||
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Depression (PHQ-9t) | Yes | Yes | Yes | Yes | ||||
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Anxiety (GAD-7u) | Yes | Yes | Yes | Yes | ||||
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Health care use (UCSDv) | Yes | Yes | Yes | Yes | ||||
APOEw status | Yes | No | No | No |
aWill be measured.
bWill not be measured.
cDXA: dual-energy x-ray absorptiometry.
dLDL: low-density lipoprotein.
eHDL: high-density lipoprotein.
fTC: total cholesterol.
gBDNF: brain-derived neurotropic factor.
hhs-CRP: high-sensitivity C-reactive protein.
iIL-6: interleukin 6.
jANU-ADRI: Australian National University-Alzheimer Disease Risk Index.
kTBI: traumatic brain injury.
lRBANS: Repeatable Battery for the Assessment of Neuropsychological Status.
mSPPB: Short Physical Performance Battery.
n6MWT: 6-minute walk test.
oE-Cog-12: 12-item Everyday Cognition Scale.
pPSQI: Pittsburgh Sleep Quality Index.
qPSS: Perceived Stress Scale.
rSF-12: 12-Item Short Form Health Survey.
sUCLA: University of California, Los Angeles, 3-item Loneliness Scale.
tPHQ-9: 9-item Patient Health Questionnaire.
uGAD-7: General Anxiety Disorder 7-item scale.
vUCSD: University of California at San Diego.
wAPOE: apolipoprotein E.
The cognitive function of the participants will be assessed using RBANS [
Neurotrack Technologies has developed a digital battery of cognitive assessments measuring attention, associative learning, memory, inhibition, executive function, and processing speed. The Neurotrack assessments were found to be valid (
Associative learning and memory will be assessed using the Item Price test. This assessment will consist of a familiarization phase in which the items (eg, various fruits and vegetables) will be presented along with their associated prices. Immediately after the familiarization phase, the participants will be presented with the items and a corresponding price. The participants will be instructed to select
Image pairs is an eye-tracking task that measures visual recognition memory and learning [
Symbol match is a processing speed and executive functioning task that uses a paired verification or rejection paradigm (forced choice). The participants will be instructed to determine whether 2 symbols are equal or unequal using a legend with 9 number or symbol pairs. The participants will be allotted 2 minutes to complete as many trials as possible. Scores will be determined by the number of correct trials minus the number of incorrect trials.
Arrow Match test is a measure of attention and processing speed. The participants will be shown 5 arrows in the middle of the screen and will be instructed to identify the direction of the middle arrow. The arrow may point in either the same direction or the opposite direction from the other arrows. The participants will be presented with 32 trials, and the scores will be reported as the number of correct responses relative to the time elapsed during all the trials.
Executive function will be assessed using the Path Points test. Similar to the paper-pencil Trail Making Test Part B [
Reaction time and inhibition will be assessed using the Light Reaction test. The participants will be presented with either a positive (green light) or a negative stimulus (red light). The participants will be instructed to press a button if the positive stimulus appears and to refrain from pressing the button if the negative stimulus appears. The average response time for reacting to the positive stimulus (green light) will be recorded.
Short Physical Performance Battery consists of 3 assessments: standing balance, usual walk time, and chair stand performance. The standing balance score will be compiled from 3 balance tests: standing with feet together, standing in a semitandem position, and standing in a full tandem position. If the participant could stand with their feet together and in the semitandem position for 10 seconds, 1 point will be given for each condition. If the participant stands for 10 seconds in the full tandem position, 2 points will be given, 1 point for 3-9.99 seconds, and 0 points if they do not hold the position for at least 3 seconds. For the assessment of usual walk time, the participants will be instructed to walk at their usual pace for 4 m. Scores will range from 0 to 4 based on the time to completion [
Cardiovascular endurance will be assessed using the 6MWT [
Hand grip strength will be assessed using a Takei hand grip dynamometer (Takei Scientific Instruments Co, Ltd). The participants will be properly fit and instructed to squeeze maximally for at least 3 seconds. Verbal encouragement will be provided. Three trials will be completed on each hand with a 60-second rest between trials. Hand grip strength is positively correlated with overall muscle strength and physical mobility [
Gait speed will be determined using 2 trials: habitual and fast. For the habitual trial, the participants will be instructed to walk 20 m at their habitual or usual walking speed. Immediately after the habitual speed trial, the participants will be instructed to walk as quickly and as safely as possible without running. Two trials will be completed for both conditions and only the middle 10 m gait speed distance will be recorded and used for all the analyses. Gait speed was previously found to be a valid and reliable measure of physical mobility [
Immediately after the gait speed trials, the participants will be instructed to repeat both habitual and fast trials while completing a serial subtraction cognitive task. The participants will be given a randomly generated 3-digit number ranging from 100 to 999 and will be instructed to begin walking immediately upon receiving their number. The participants will walk the entire distance while subtracting 3 from their assigned number aloud. Both, time to cover the 10 m distance and correct and incorrect numbers will be recorded [
Lower extremity muscular power will be assessed using a power chair stand [
ANU-ADRI is an evidence-based 79-item risk assessment tool designed to predict the risk of future AD development. ANU-ADRI collects information on education, BMI, cholesterol, diabetes, history of traumatic brain injury, depression, physical activity, cognitive engagement, social network, fish intake, alcohol consumption, smoking, and pesticide exposure [
Anxiety will be assessed using the General Anxiety Disorder 7-item scale [
The University of California, Los Angeles, 3-item Loneliness Scale [
Health-related quality of life will be measured using the 12-Item Short Form Health Survey, which is a valid and reliable measure of health-related quality of life in many study populations [
Perceived stress will be assessed using the Perceived Stress Scale [
Physical activity will be assessed using the International Physical Activity Questionnaire, which is the physical activity component of the ANU-ADRI. This survey is a valid and reliable self-report tool for quantifying moderate, vigorous, and sedentary behaviors [
The health care use form of the University of California at San Diego will be used to quantify how frequently the participants have visited their physician or used any form of health care within the previous 3 months. Higher values indicate more health care use during the time frame [
Sleep quality will be assessed using the Pittsburgh Sleep Quality Index. This 9-item assessment produces a score ranging from 0 to 27, with higher scores indicating poorer sleep. Individuals scoring ≥5 are deemed poor sleepers [
Depression will be assessed using 2 surveys. The Patient Health Questionnaire is a 9-item questionnaire with scores ranging from 0 to 27. Higher scores indicate higher levels of depression [
The 12-item Everyday Cognition scale is a brief questionnaire designed to detect cognitive and functional decline. This scale has been shown to correlate with functional measures and neuropsychological scores in people with normal cognitive function, mild cognitive impairment (MCI), and AD [
Blood sample will be collected at each of the 4 study visits. High-sensitivity C-reactive protein, interleukin-6, and brain-derived neurotrophic factor will be analyzed by a third-party laboratory. Cholesterol (total, HDL, and LDL), triglycerides, and blood glucose levels will be analyzed in whole blood using a Cholestech LDX system (Abbott Laboratories). Whole blood will be collected in a 40 µL capillary tube, immediately transferred into a Cholestech cartridge, and analyzed. Cholestech LDX values are valid and reliable for the assessment of triglycerides, LDL, HDL, and total cholesterol [
Before the recruitment of participants into the intervention, all the study ID numbers were randomly preassigned. A member of the research team assigned each study ID to a number generated by a random numbers table. As participants (who met all the inclusion criteria and none of the exclusion criteria and signed the informed consent form) were enrolled in the study, they were assigned a study ID number.
The participants randomly allocated into the HC arm of the study will be assigned a personal health coach to work with for the duration of the study. HC will take place remotely through videoconferences and asynchronous chat messages and focus on helping the participants improve their brain health by working on the following lifestyle domains: nutrition, physical activity, sleep, stress, social engagement, and cognitive activity. HC will communicate with the participants about each of these modifiable risk factors and then tailor their recommendations and communications to the specific lifestyle areas needed for each participant. HC participants will also be provided access to a cognitive health app (Citruslabs), through which they can access cognitive training activities, workout routines, and recipes. HC is different from traditional interventions used in RCTs. Instead of testing a uniform program to fit all the participants, the HC recommendations and communications will be tailored by the coach to fit each participant’s unique needs.
The HC will actively reach out to participants 1-2 times per week through asynchronous messages and will provide articles on various lifestyle modifications, such as nutrition information and physical activity, based on the focus for each participant. In addition, the participants will have unlimited access to their coach to ask questions or obtain the coach’s recommendations. Meetings with the coach will be scheduled on a monthly basis through videoconference or phone to assess the progress toward the goals, discuss any barriers they have encountered, and strategize personalized ways to attain the goals. The lifestyle domains will be chosen based on a combination of the participant’s preferences and the coach’s recommendations. For example, if the HC identifies nutrition as the primary source of need for a participant but the participant is not ready to work on that area, the HC will make alternative recommendations to meet the participant where they feel ready to make a change.
The HC intervention is designed to support participants through the recommended lifestyle changes to improve brain health and reduce dementia risk. The topics that will be discussed during the initial intake session include (1) description of the HC process, (2) description of lifestyle domains and how they are related to brain health, (3) gathering information from the participant on which lifestyle domains they seek and are willing to improve, (4) assessing motivation and readiness for change, and (5) assisting the participant for creating a vision for their future, including appropriate goal-setting. Although the monthly follow-up coaching sessions can differ between participants, they will typically include (1) reassessing goals and making appropriate modifications to meet personal health goals and (2) supporting the participant in overcoming the challenges they meet throughout their personal journey.
Participants randomly assigned to the HE control group will receive biweekly emails including information on how to change their lifestyle to improve their brain health. To independently evaluate the efficacy of the intervention, the same lifestyle domains will be covered in both arms of the study. These lifestyle domains include physical activity, dietary habits, sleep, stress, social engagement, and cognitive activity. Throughout the duration of the intervention, the participants will only have access to the study staff during their on-site testing sessions. After the intervention, the number of articles opened by the participant will be tallied to determine engagement from the control group.
Participants were recruited in northwest Arkansas using local radio, email, social media advertisements, and word of mouth. The participants who met all the inclusion criteria and none of the exclusion criteria were randomly assigned to one of the groups before any assessments were completed.
The goal sample size for this study is approximately 200 participants. This sample size is considered sufficient to achieve random assortment, which was validated after examining the baseline characteristics of both groups. Cross-sectional, between-group differences in the baseline ANU-ADRI scores will be assessed using analysis of variance (ANOVA). Longitudinal studies following cognitively intact older adults have documented a 0.8 RBANS standard score change (SD 13.8) over a 12-month period [
Using the results of previous web-based intervention studies designed to reduce AD risk in an RCT design [
Exploratory analyses will be performed on an intent-to-treat basis. One-way ANOVA will be used to compare the groups on functional fitness; biomarker measures; health-related variables; and digital, cognitive assessments at baseline. In addition, sex differences in baseline characteristics and change scores will be evaluated using a 2×2 (group and sex) ANOVA. Repeated measures ANOVA will be used to determine the differences over time between the groups. APOE status and the presence of homozygous E4 alleles will be used as a dichotomous variable and as a covariate for change in results after the intervention.
The study was approved by the University of Arkansas Institutional Review Board. All participants signed an approved consent form in accordance with the ethical standards of Helsinki.
The enrollment funnel for the DCMARVel trial is shown in
Participant screening and enrollment funnel.
Baseline characteristics (N=204).
Variables | Health education (n=101) | Health coaching (n=103) | Total (N=204) | |
Age (years), mean (SD) | 61.4 (8.9) | 62.4 (7.6) | 61.9 (8.3) | .38 |
Sex (female), n (%) | 77 (76.2) | 75 (72.8) | 152 (74.5) | —b |
Ethnicity (White), n (%) | 98 (97) | 100 (97.1) | 198 (97.1) | — |
ANU-ADRIc total, mean (SD) | −1.61 (7.34) | −1.75 (7.32) | −1.68 (7.31) | .90 |
ANU-ADRI risk, mean (SD) | 8.97 (5.91) | 8.41 (5.57) | 8.68 (5.73) | .48 |
ANU-ADRI protective, mean (SD) | −10.38 (4.49) | −10.15 (4.60) | −10.26 (4.54) | .72 |
aObtained from 2-tailed
bNo statistical analysis was performed.
cANU-ADRI: Australian National University-Alzheimer Disease Risk Index.
To our knowledge, this study is the first large-scale 2-year RCT to examine the effect of a digital multi-domain lifestyle intervention on reducing AD risk among a population that includes adults as young as 45 years. Improving the modifiable risk factors for AD has the greatest potential to impact disease development when implemented early and in a targeted manner and effective treatments hinge upon early identification and appropriate lifestyle modification. Although several single-domain interventions have been implemented with little success, multi-domain interventions have demonstrated greater levels of improvement [
The HC intervention will address 6 lifestyle domains that have been linked to the development of dementia later in life: diet, exercise, sleep, stress, social engagement, and cognitive activity. In addition to receiving HE material similar to the control group, participants in the intervention arm will work with a health coach to develop and implement changes to the lifestyle areas that they are ready to work on. The tailored nature of the program is designed to maximize the behavior change outcomes.
Dietary habits are an important modifiable risk factor for dementia. The Mediterranean-DASH intervention for neurodegenerative delay (MIND) diet is recommended to participants based on its positive effects on brain health [
Habitual physical inactivity is associated with many chronic health conditions such as type 2 diabetes, cardiovascular disease, and hypertension [
Sleep is an important aspect of both brain health and overall health. Aging is often associated with changes in sleep patterns [
Stress is a multifactorial response to both internal and external stimuli. However, exposure to chronic stress can result in major illnesses and ailments [
Loneliness has recently been identified as a positive predictor of dementia among older adults. After a 3-year follow-up, older adults with self-reported feelings of loneliness and living alone showed an approximately 2.5-fold increase in the risk of dementia [
Low cognitive engagement has previously been linked with increased risk of dementia [
The results of this study can produce a novel and highly scalable intervention strategy to reduce the risk of cognitive decline before MCI or AD diagnoses occur. The primary outcome in the DCMARVel trial is AD risk reduction as determined by ANU-ADRI [
6-minute walk test
Alzheimer disease
analysis of variance
Australian National University-Alzheimer Disease Risk Index
apolipoprotein E
Digital, Cognitive, Multi-domain Alzheimer Risk Velocity
health coaching
high-density lipoprotein
health education
low-density lipoprotein
mild cognitive impairment
Mediterranean-DASH intervention for neurodegenerative delay
Repeatable Battery for the Assessment of Neuropsychological Status
randomized controlled trial
ENM, JMG, and JM are employed by Neurotrack. They receive salary and hold equity in the company.