Alzheimer disease and Alzheimer disease–related dementias (AD/ADRD) are debilitating neurodegenerative disorders that impair cognitive and daily functioning [1]. An estimated 50 million people are living with AD/ADRD worldwide, with 10 million new cases occurring annually [2-4]. AD/ADRD places an immense burden on individuals, families, and health care systems. The economic toll of family and unpaid caregiving for AD/ADRD was US $346.6 billion in 2023 [5]. In the early stages of AD/ADRD, approximately half of adults aged ≥65 years perceive subjective cognitive decline (SCD) [6,7] in memory or other cognitive domains before neurodegeneration can be detected through cognitive testing [8,9]. SCD is associated with a greater likelihood of underlying AD/ADRD biomarker pathology and increased risk for future cognitive decline and AD/ADRD [10-13]. This preclinical stage is a critical window to engage older adults in preventive interventions that aim to modify AD/ADRD risk factors.

Growing research indicates that multiple lifestyle behaviors are important for AD/ADRD prevention [14-21]. In 2020, the Lancet Commission on Dementia identified 12 modifiable risk factors accounting for 40% of AD/ADRD cases worldwide: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, low social contact, excessive alcohol consumption, a history of head injury, and exposure to air pollution [22]. The commission also highlighted the need for further research on additional lifestyle risk factors such as poor sleep [23-25], diet [23,26], and mental activity [27,28], which may influence AD/ADRD risk but have shown mixed findings [29]. Multidomain trials targeting modifiable lifestyle risk factors identified in the Lancet report have demonstrated the potential to improve cognition among older adults with early cognitive decline [30,31]. However, not all multidomain trials have reported positive results [32-34]. Trials have also failed to modify behaviors [33], or they have inconsistently reported lifestyle outcomes [30]. Complex and time-intensive intervention designs hindered participant adherence [35,36] and limit future implementation. Additional research is needed to develop more effective and practical interventions that promote sustained engagement and adherence to AD/ADRD prevention strategies among older adults.

Mindfulness practices may help address challenges in modifying lifestyle behaviors and offer direct brain health benefits. Mindfulness is commonly defined as the practice of nonjudgmental awareness of the present moment [37]. Mindful self-regulation theory suggests that mindfulness involves several self-regulation processes (eg, emotion regulation, cognitive control, and self-monitoring) that enhance one’s ability to cope with urges (eg, overeating or avoiding exercise) and make healthier lifestyle choices [38-40]. Mindfulness practice is positively associated with measures of enhanced brain structure [41-43] and cognitive function [41,44-48]. In addition, mindfulness is associated with reductions in psychological symptoms, such as depression, anxiety, and attitudes and worries regarding AD/ADRD [49-52], which are independent risk factors for AD/ADRD [53-56] and an inactive lifestyle [57]. Mindfulness is feasible and acceptable for older adults, including individuals with SCD [38,52,58]. Prior research suggests that cognitive benefits associated with mindfulness can be observed with brief practice [59-61], suggesting that mindfulness is amenable to time-limited interventions. Despite these advantages, mindfulness has been overlooked in behavior modification AD/ADRD prevention interventions.

Our interdisciplinary team has developed the first group mindfulness-based lifestyle intervention (My Healthy Brain [MHB]) that aims to modify early risk for AD/ADRD. We conducted a series of preliminary studies to develop MHB following the National Institutes of Health (NIH) Stage Model [62], an iterative framework for guiding behavioral intervention development and testing, from pilot studies to implementation and dissemination (Figure 1). First, our systematic review and meta-analysis (we analyzed 79 studies with 9233 participants) found moderate- to high-quality evidence that mindfulness-based interventions were associated with significant improvements in multiple lifestyle behaviors linked to brain health, including sleep, physical activity, alcohol use, and tobacco cessation [63]. Second, we conducted iterative studies of older adults with AD/ADRD risk factors to determine the best delivery modality and strategies to incorporate mindfulness into lifestyle behaviors. Preliminary studies included (1) an in-person clinical pilot (N=24) [64], (2) a telehealth group case series (N=7) [65], and (3) a mixed methods study to adapt the program via qualitative focus groups (N=11) and conduct a feasibility pilot with exit interviews (N=10) [66]. MHB met benchmarks set a priori for feasibility, credibility, satisfaction, and safety (there were no adverse events). We observed preliminary improvements (moderate to large effects) in subjective and objective measures of cognitive function, physical activity, sleep, and proposed mechanisms. Exit interviews confirmed the satisfaction with mindfulness and feasibility with technologies to support behavior change (monitoring steps via an activity watch) and remote delivery (Zoom; Zoom Video Communications, Inc). Finally, we conducted a qualitative study with health care professionals caring for older patients (N=26) to address barriers to implementing study procedures (eg, recruitment, enrollment, and retention) and maximizing diversity to prepare for the first feasibility randomized controlled trial (RCT) of MHB [67].

Building upon our preliminary studies, we report on the improved protocol and initial launch of the first feasibility RCT of MHB (NIH stage 1B). We are enrolling 50 older adults (aged ≥60 y) with SCD and modifiable AD/ADRD lifestyle risk factors. Participants are randomized to MHB or a time- and attention-matched education control (health enhancement program [HEP]) [68,69], both delivered in telehealth groups over 8 weeks. The primary aim is to assess the feasibility, acceptability, appropriateness, credibility, satisfaction, and fidelity of MHB against established Go–No-Go benchmarks [64,70-74]. The secondary aim is to investigate preliminary improvements in cognitive and lifestyle outcomes and engagement in proposed mechanisms. The results will inform the first efficacy RCT of MHB and mechanistic testing of cognitive and lifestyle outcomes.

We are conducting a virtual, single-blind, feasibility RCT of the MHB intervention versus the HEP [68,69] education control (N=50). Our study is consistent with the research objectives and activities specified in stage 1B of the NIH Stage Model [62]. NIH stage 1 focuses on intervention development, testing, refinement, and modification. NIH stage 1B activities emphasize the refinement of intervention and training materials, feasibility and pilot testing, and early attention to implementation. As such, our study is designed to confirm the feasibility of MHB and assess engagement in intervention outcomes and hypothesized mechanisms before conducting a fully powered efficacy RCT [75-77]. All procedures described herein are conducted fully remotely, allowing for both local and national recruitment. We followed the National Council on Aging guidelines for using technology with older adults [78] and our established digital health trials [66,70,74,79-92]. Figure 2 presents the study flow.

We preregistered our RCT on ClinicalTrials.gov (NCT05934136) before enrolling the first participant.

The Mass General Brigham (MGB) institutional review board (IRB) approved all study procedures (2023P001770). All participants review and sign written informed consent with a clinical research assistant (RA) before completing study procedures. Consent informs participants that, with any group-based intervention, there may be confidentiality and privacy risks. To minimize these risks, we discuss the importance of confidentiality at the start of each group; request that participants attend the session from a private location; and all data are deidentified, maintained in a secured location, and only accessed by IRB-approved members of the research team. Participants are compensated up to US $220: US $30 for before the intervention assessments, US $60 for after the intervention assessments, US $90 for 6-month follow-up assessments, with an additional US $40 for 7 out of 7 valid days of Garmin Vivosmart 5 wear during the before the intervention assessment period. This compensation strategy is meant to optimize participant engagement and motivation for 6-month follow-up assessments.

Participants are older adults (aged ≥60) who are at early risk for AD/ADRD as determined by the presence of SCD [8], have no cognitive impairment (Telephone Interview for Cognitive Status score >30) [93], and have modifiable AD/ADRD risk factors (Cardiovascular Risk Factors, Aging, and Incidence of Dementia [CAIDE] score ≥6) [94,95]. Textbox 1 shows our full inclusion and exclusion criteria and rationales, which we have refined through our previous pilot studies [64-66]. These eligibility criteria were informed by similar lifestyle AD/ADRD prevention trials [30,31,35] and behavioral interventions for older adults [74,81,83,92,96].

Our recruitment strategy incorporates a combination of hospital partnerships, community outreach, and internet-based recruitment methods. Through our preliminary studies, we developed partnerships with several MGB clinics that are directly involved in the care of older patients with SCD. The clinics represent expertise in geriatrics, geriatric psychiatry, neurology, neuropsychology, memory care, and integrative medicine. To promote the study within our hospital, we have engaged clinic leadership, presented in team meetings, and distributed our IRB-approved flyer to providers and clinic waiting areas. The flyer contains study contact information and a QR code to an eligibility self-screener. In addition, patients can contact the study through a hospital web-based recruitment platform (MGB Rally). We aim to maximize the inclusion of older adults from diverse and underserved backgrounds to address disparities in AD/ADRD [99,100] and underrepresentation in prevention clinical trials [101,102]. First, we have proactively formed collaborations with MGB clinics that serve more diverse patients. Second, we have engaged community organizations and Councils on Aging (commonly known as “senior centers”) in Massachusetts. Community outreach consists of engaging community leadership, disseminating recruitment materials, and conducting public events (eg, networking nights and educational talks). We are specifically targeting outreach to underresourced communities of older adults in Massachusetts who face significant health disparities and heightened risk factors for AD/ADRD [103]. Third, we have consulted with our center’s Community Engagement Core on evidence-based recruitment strategies [104]. Fourth and last, we have expanded our outreach nationally via social media platforms, web-based study postings (eg, ClinicalTrials.gov and Alzheimers.gov), and articles and presentations developed for public audiences.

The RA logs all referral information in a standardized REDCap (Research Electronic Data Capture; Vanderbilt University) [105] database. Participants have the option to complete an initial screening survey independently or by telephone with the RA. The RA contacts all potentially eligible participants to answer questions about the study, collect availability for groups, and assess technology access and readiness. Individuals who do not meet study criteria are offered resource sheets developed for older adults with SCD. The principal investigator (RAM) reviews all eligibility decisions and consults with the multidisciplinary study team if needed. After group times have been set, the RA meets with participants individually over Zoom to schedule the before the intervention assessments, review study technology, and obtain electronic informed consent via REDCap. The RA uses secure email to send confirmation and Zoom links for the before the intervention assessments.

This study was funded by a National Institute on Aging Mentored Patient-Oriented Research Career Development Award (K23; 1 K23 AG075257-01; September 2022). The study was approved by the IRB in October 2023. We began recruitment in January 2024. As of June 1, 2024, a total of 225 individuals had inquired about the study via self-referral or referral from a clinician or community partner. We made initial contact and conducted screenings with 213 (94.7%) of the 225 individuals; 25.6% (40/156) met the eligibility criteria. Of the 40 eligible participants, 21 (52.5%) were enrolled in 2 group cohorts, 17 (42.5%) were on hold for future group cohorts, and 2 (5%) withdrew before enrollment. Primary reasons for ineligibility included low AD/ADRD risk (CAIDE score <6; 54/116, 46.6%), active lifestyle (>5000 average steps per day and ≥30 minutes of exercise per day; 26/116, 22.4%), no self-reported SCD (18/116, 15.5%), age <60 years (16/116, 13.8%), regular mindfulness practice (8/116, 6.9%), and clinically significant cognitive impairment (Telephone Interview for Cognitive Status score <31 out of a maximum possible 41 points; 5/116, 4.3%).

All 21 enrolled participants were randomized to MHB (n=11, 52%) or the HEP (n=10, 48%) across 2 group cohorts (cohort 1: n=9, 43%; cohort 2: n=12, 57%). All participants completed before the intervention assessments. No participants have dropped out after enrollment. All participants in our first cohort completed ≥6 out of 8 sessions of either MHB or the HEP (including minimal makeup sessions) and after the intervention assessments (9/9, 100%). One participant requested to skip the HEP session on substance use due to a traumatic family history. The intervention for our second cohort (12/21, 57%) is ongoing (5 out of 8 sessions completed; 100% attendance with minimal makeup sessions). Across both cohorts, adherence rates are high for the Garmin Vivosmart 5 (128/147, 87.1% total weeks) and daily surveys (105/122, 86.1% total weeks). We plan to complete enrollment by December 2024 and data analyses by December 2025.

Sample characteristics for enrolled cohorts 1 and 2 are presented in Table 3.

SCD represents a critical opportunity for early intervention to modify risk factors for AD/ADRD. MHB addresses this gap by offering a novel group mindfulness-based lifestyle program tailored to older adults with SCD. Single-arm open pilot studies (NIH stage 1A) have demonstrated the feasibility and acceptability of MHB, indicating its potential to bypass challenges to lifestyle behavior modification and improve cognitive outcomes among older adults. These preliminary studies also revealed barriers to participation that must be addressed during the design and execution of the first RCT of MHB before conducting fully powered trials or implementing the program in clinical care.

The primary aim of this feasibility RCT is to establish the feasibility, acceptability, appropriateness, credibility, satisfaction, and fidelity of the MHB intervention compared to the HEP active control (NIH stage 1B). Our secondary aim is to explore preliminary signals of improvement in outcomes and hypothesized mechanisms (Table 1 and Figure 3). Testing these aims and our ability to randomize participants to MHB versus the HEP will serve as a “dress rehearsal” for a subsequent efficacy RCT. In addition, this RCT will provide valuable insights into the feasibility of integrating multiple digital health technologies into a lifestyle trial for older adults with SCD. If feasible, the novel integration of passive activity sensors, repeated mobile cognitive assessments, and daily surveys offer a comprehensive framework for monitoring adherence and understanding individual responses to lifestyle interventions and the mechanisms of action. This is notable because the pathways by which lifestyle interventions may improve cognitive outcomes and prevent AD/ADRD among older adults with SCD are poorly understood.

We have made several changes to our study protocol (Multimedia Appendix 1) guided by our qualitative studies [67]. Using implementation science frameworks [205-207] and the socioecological model [208], the protocol changes and strategies aim to maximize RCT outcomes, increase sample diversity within our RCT, and reduce barriers to AD/ADRD prevention efforts [209-212]. Initial observations suggest that our protocol changes and strategies have been effective. We have observed a high volume of inquiries, indicating that our outreach efforts have been successful and that older adults are interested in participating in the study. Participant adherence to both programs is notably high, with positive engagement in the mindfulness and behavior change skills taught in MHB. Preliminary Garmin Vivosmart 5 and daily survey adherence data are also promising but must be confirmed upon study completion. Providing individualized support and devices at no cost has enabled us to include and retain older adults with limited technological access or proficiency [209,210,213]. To date, the enrolled participants predominantly represent White, well-educated women. In our next group cohorts, we will prioritize the inclusion of racial and ethnic minoritized older adults to address their underrepresentation in prevention RCTs and their increased risk of AD/ADRD [101,102]. We are conducting broader outreach, including both professional and community groups, to further increase awareness and diverse participation [214,215]. The feasibility RCT will provide initial information on our ability to engage older adult communities in AD/ADRD prevention research.

Despite the protocol improvements, several limitations remain and are outlined in the following subsections (additional limitations may arise during the execution of our trial).

The MHB feasibility RCT represents a significant step toward developing practical, evidence-based interventions for early AD/ADRD prevention. By addressing key benchmarks and engagement in intervention targets, this study lays the groundwork for larger trials aimed at validating the potential long-term benefits of mindfulness-based lifestyle programs in reducing dementia risk. Following the NIH Stage Model, the next phase of intervention development will evaluate MHB versus the HEP in a larger RCT and more diverse sample (NIH stage 2). We will rigorously test the superiority of MHB versus the HEP in enhancing cognitive and lifestyle outcomes among older adults with SCD and modifiable AD/ADRD risk factors. If successful, MHB could provide an effective and scalable intervention for reducing AD/ADRD risk, leveraging digital health technology to promote sustained behavior change and brain health.