Study design overview

Combating Alzheimer’s through Sleep and Exercise (CASE) is a single-center, three-arm, randomized trial that will investigate the effects of sleep, exercise, and a combination of these on cognitive function as well as brain and cardiometabolic biomarker outcomes in older adults with and without MCI. Participants will be randomly assigned via Research Electronic Data Capture (REDCap [18, 19]) to one of three groups: (1) exercise-only, (2) sleep-only, or (3) combined sleep and exercise. Each group will receive the following intervention-specific digital tools: (1) all groups will receive a Fitbit to continuously track physical activity, including the tracking of all in-person, biweekly, 60-minute exercise interventions; (2) the sleep-only and sleep + exercise groups will receive the Elemind Neuromodulation headband for personalized acoustic stimulation; and (3) the sleep-only and sleep + exercise groups will receive a Lys device for monitoring light exposure.

The intervention will span 8 weeks and will follow structured phases, including screening, baseline assessment, intervention, and follow-up. Full Digital Neuro-Signature Platform augmented reality cognitive assessments will be used to assess cognition at baseline and week 8 (post-intervention) as well as biweekly as brief pulse assessments throughout the trial duration. Blood-based biomarkers will be collected via venipuncture at Quest Diagnostics at baseline and post-intervention under standardized fasting conditions. Specifically, in order to maximize participant safety and minimize any potential influences of acute exercise [20], the pre-intervention blood draws will be obtained no sooner than 24 hours and no later than seven (7) days before the initiation of the first exercise session, and post-intervention blood draws will be obtained within 24–48 hours after completion of the final exercise session. No blood draws will occur on the same day as in-lab exercise. Data from digital devices will be temporally synchronized using structured protocols to support integrated analysis, and raw sleep data will be reviewed for artifacts, with re-instruction provided for invalid nights. Patient-Reported Outcomes Measurement Information System (PROMIS) surveys [21] and validated physical activity questionnaires (including the Physical Activity Scale for the Elderly (PASE [22]) and the Community Healthy Activities Model Program for Seniors (CHAMPS [23])) will be administered via REDCap at baseline (week 0) and at week 8 during the in-person visits. The CASE study is designed to assess adherence, detect early efficacy signals, and explore behavioral mechanisms that may prevent or delay AD through modifiable lifestyle-based behavior interventions.

Study proceduresParticipants

Eligible participants must meet all of the following: (1) 55–80 years of age, reflecting growing evidence that individuals may experience increased AD risk starting in midlife [24, 25]; (2) able to safely perform moderate-intensity exercise as per the Physical Activity Readiness Questionnaire (PAR-Q, a validated exercise readiness questionnaire [26]); (3) able to wear and use Fitbit wristwatch and/or the Elemind Neuromodulation headband and Lys devices; (4) able to operate a digital device, such as mobile phone or computer; (5) able and willing to provide venous blood samples; (6) able to understand and speak English fluently (currently, there remains a lack of validated, multilingual versions of the Digital Neuro-Signature Platform and associated study interfaces; presently, such validated tools are only available in English, and the utilization of non-validated translations may introduce measurement bias, particularly regarding cognitive outcomes); (7) able to self-report a history of cognitive changes or impairment; and (8) be cognitively able (including those with MCI) and willing to provide informed consent.

Prospective participants will be excluded in the case of (1) severe mobility limitation(s) that prevent(s) safe participation in moderate exercise protocols; (2) unstable or uncontrolled medical conditions (e.g., recent cardiovascular event (≤ 6 months), cerebrovascular accident or transient ischemic attack (≤ 6 months), active cancer, or uncontrolled diabetes) that pose safety concerns; (3) inability to complete intake screening procedures; (4) severe uncorrected hearing impairment, particularly if it precludes effective utilization of the Elemind Neuromodulation headband, and/or vision impairment that interferes with digital device usage or in-person exercise guidance; (5) determined to have Alzheimer’s/dementia based on performance on the Quick Mild Cognitive Impairment (QMCI [27]; see Table 1); (6) inability or unwillingness to learn or engage with digital devices (e.g., smartphone, Fitbit, Elemind, or Lys), even with staff support; (7) regular pre-study engagement in ≥ 150 minutes of moderate-level and/or ≥ 75 minutes of vigorous-level exercise per week based on Fitbit data obtained during the initial 7-day onboarding screening period; (8) determined to have adequate sleep metrics, including duration (mean 7–9 hours) and quality (sleep efficiency ≥ 80% [28]), pre-intervention based on Elemind Neuromodulation headband data obtained during the initial 7-day onboarding screening period; and (9) current usage of disease-modifying therapy targeting amyloid (e.g., anti-amyloid monoclonal antibodies) or tau.

Table 1 Quick Mild Cognitive Impairment score thresholds by cognitive statusParticipant recruitment

A total of 60 participants comprised of approximately 30 CN older adults and 30 older adults with MCI will be enrolled in this study. Recruitment strategies will consist of a combination of the following:

1)

Participants will be recruited from existing studies and research registries maintained by the Translational Sleep and Circadian Sciences (TSCS) Laboratory at the University of Miami Miller School of Medicine. All individuals considered for enrollment will have previously consented to be contacted for future research opportunities. Initial contact will be made via phone by trained study personnel to confirm interest and screen for eligibility.

2)

In addition, recruitment will include referrals for prospective participants with an MCI diagnosis from the Division of Cognitive Neurology at the University of Miami.

3)

Moreover, flyers and social media advertisements will be distributed throughout southern Florida to further aid in recruitment efforts.

4)

This trial will participate in the University of Miami’s Consent to Contact program, which allows approved researchers to access a database of University of Miami Health System patients who have agreed to be contacted about participating in clinical research studies.

Recruitment and enrollment procedures will comply with all institutional and federal guidelines, including the Health Insurance Portability and Accountability Act (HIPAA), to ensure privacy and confidentiality of all protected health information that is obtained. Eligible participants will be equally randomized (n = 20 per group) into three study arms: sleep-only, exercise-only, or combined sleep and exercise. Stratified randomization by cognitive status will be employed to ensure balanced representation across groups (i.e., each group will be comprised of 10 CN participants and 10 participants with MCI).

Screening and consent

A trained research assistant will conduct a brief phone pre-screening with all interested prospective participants. During this call, the research assistant will collect key demographic information (e.g., age, sex, education level, and smartphone ownership) and administer two validated screening tools: the Quick Mild Cognitive Impairment screen (QMCI, a clinician-administered tool used to assess objective cognitive status [27]) and the Physical Activity Readiness Questionnaire (PAR-Q, which evaluates the participant’s ability to safely engage in moderate exercise [26]; (see Table 2)). Both assessments will require fewer than five minutes to complete. Participants must achieve a QMCI score at or above the specified age- and education-adjusted scoring thresholds that indicate either CN or MCI status (see Table 1 [29, 30]) and report no contraindications to performing moderate-intensity exercise on the PAR-Q. Subjects who score below these thresholds will be excluded from the trial; no borderline adjudication process will be applied to ensure clarity and reproducibility.

Table 2 Screening questionnaires

Individuals meeting these pre-screening criteria will then be scheduled for an in-person screening visit to provide written informed consent and further assess eligibility criteria via a 7-day screening period. After signatures are obtained, each prospective subject will be provided with a copy of the signed informed consent document. All procedures have been approved by the University of Miami Institutional Review Board (IRB) requirements and federal privacy protections and will be conducted in accordance with the Helsinki Declaration. Thereafter, prospective participants will be randomized into one of three arms and will receive intervention-specific, wearable devices and will be instructed on how to use these devices. All prospective participants will receive Fitbit devices, while those assigned to sleep or sleep + exercise intervention will receive an Elemind Neuromodulation headband to be used daily without stimulation during the initial 7-day screening period and a Lys device. Prospective participants in all groups will be asked to wear the Fitbit device continuously to establish baseline physical activity levels and to confirm sedentary to lightly active physical activity levels in order to satisfy eligibility criteria for those assigned to interventions that involve exercise, and those assigned to the sleep-only or sleep + exercise interventions will be asked to wear the Elemind Neuromodulation headband without stimulation while the device actively collects sleep data for seven consecutive nights to establish baseline sleep patterns, ensure comprehension of and comfortability with wearing the headband; additionally, this will confirm subquality sleep pre-intervention to satisfy eligibility criteria for those assigned to groups that involve the sleep intervention.

Prospective participants who are assigned to the sleep or sleep + exercise interventions and are determined to have good quality sleep after the onboarding period as defined by the eligibility criteria will either be reassigned to the exercise-only intervention (if also found to engage in < 150 minutes of moderate-level or < 75 minutes of vigorous-level activity weekly via the Fitbit) or will be excluded from further participation and given $20 compensation. Prospective participants who are assigned to the exercise or sleep + exercise interventions and who are found to be active or very active (as defined by the eligibility criteria) will either be reassigned to the sleep-only intervention and be invited to undergo an additional 7-day onboarding screening duration with the Elemind Neuromodulation headband to determine sleep-specific eligibility or will be excluded from further participation and given $20 compensation. Prospective subjects who agree to undergo an additional 7-day screening period and are deemed to have good quality sleep pre-intervention at baseline will also be excluded from participation and given $20 compensation.

Once a participant has completed the 7-day onboarding screening period and found to be eligible, subjects will be prompted to set up an appointment with Quest Diagnostics. Sample analysis will be available to the participant through email and/or through the Quest Diagnostics app within a few days, and participants will consent to share the data with the University of Miami study team. Intervention (week 0) will begin as soon as possible after this process is complete. Another identical procedure will be initiated as soon as possible after the intervention period is complete. All procedures will comply with the University of Miami Institutional Review Board (IRB) requirements and federal privacy protections. Subsequent to completing the onboarding screening period, eligible participants will be invited to complete an in-person baseline visit.

Randomization

The design will follow CONSORT randomization guidelines [31]. Participants will be eligible for randomization once all baseline questionnaires are completed. Blocked randomization will be conducted using a randomization table. Subjects in each block will be assigned to one of three intervention arms, ensuring equal allocation between CN and MCI subjects in each group.

Baseline and follow-up visits

Data will be collected at baseline, biweekly, and at the 8-week follow-up to assess changes in sleep, exercise, biomarkers, and cognition. After consent and randomization, participants will be onboarded in person to each intervention-specific device and observed for a 7-day period prior to the baseline visit to establish baseline sleep patterns and/or physical activity levels relevant for each assigned intervention and to ensure all eligibility criteria are satisfied. Cognitive function will be measured using an augmented reality-based tool at baseline and week 8, with brief pulse assessments administered twice-weekly throughout the intervening period. Blood biomarkers will be collected via venipuncture at Quest Diagnostics (baseline and week 8). Physical activity and sleep data will be respectively monitored using Fitbit (all groups) and the Elemind headband (sleep and sleep + exercise groups), and light exposure will be tracked via the Lys device (sleep and sleep + exercise groups). Participants will also complete validated self-report surveys (e.g., PASE, CHAMPS–MET, PROMIS instruments) to capture psychosocial and behavioral variables at weeks 0 and 8. This multimodal approach will enable temporally-aligned, comprehensive data capture across digital and self-reported domains (see Table 3).

Table 3 Timeline of questionnaires provided

Participants who provided written consent and are found to be eligible for participation at the conclusion of the 7-day onboarding screening period will undergo the following procedures in accordance with the intervention to which each subject was assigned:

Interventional group 1 (exercise only)

Participants randomized to the exercise-only group will engage in an 8-week, home- and site-based exercise intervention designed for older adults across a range of cognitive and physical function levels. All site-based sessions will occur in-person at the study facility under supervision of trained staff. Each week, participants will attend two 60-minute structured exercise sessions, consisting of aerobic training and resistance training. On the remaining five days when subjects will not engage in structured exercise, subjects will be asked to engage in 30 minutes of moderate-intensity walking activities. In-lab exercise protocols will be fully standardized to ensure consistency of exercise dosage and fidelity across participants. The target exercise load will be 270 minutes of moderate-intensity exercise weekly for 8 weeks. Although considered short-term exercise, this exercise dosage has been shown to improve cerebral blood flow, regional brain volume, and brain-protective trophic factors [32].

Participants will begin with a 7-day onboarding period, during which participants will wear the Fitbit continuously to establish baseline physical activity levels and to ensure initial eligibility criteria are satisfied. Subsequent to this initial observation and screening phase, subjects will participate in biweekly, in-person exercise sessions, which will be comprised of 60 minutes of stretching, aerobic, and resistance training exercises. Specifically, exercise sessions will consist of a 10-minute warm-up, followed by 20 minutes of moderate-intensity aerobic exercise at 60–75% of estimated maximum heart rate (MHR). MHR will be estimated using Tanaka’s formula (maxHR = 208-(0.7*age)) [33], and the target heart rate (THR) will be calculated using Karvonen’s formula to account for resting heart rate (RHR), where THR = ((MHR-RHR)*% intensity) + RHR [34]. Moderate-intensity aerobic training will be followed by 20 minutes of resistance training of major muscle groups with an emphasis on lower extremity resistance training one day each week and upper extremity resistance training at the second in-person session weekly. Exercise load will be at 60–80% of an estimated one repetition max using American College of Sports Medicine Guidelines [35]. Muscle groups that will be trained include biceps, triceps, deltoid, and latissimus dorsi for the upper extremity, and quadriceps, hamstrings, and gastrocnemius/soleus for the lower extremity. Resistance training exercises targeting the trunk will also be incorporated. Each exercise session will then conclude with 10 minutes of post-exercise stretching.

Home-based protocol

In addition to the twice-weekly, site-based exercise sessions, participants will be asked to include 30 minutes of walking at moderate intensity on the remaining five days each week when subjects do not complete the biweekly, in-person exercise sessions.

Assessment of aerobic capacity

Aerobic capacity will be measured at baseline and after 8 weeks of exercise using the six-minute walk test (6MWT). The 6MWT accurately estimates maximal oxygen uptake capacity (VO2max) using regression equations, including distance walked, sex, age, and body mass index [36].

Cognitive pulse assessments

Participants will complete twice-weekly, brief cognitive pulse assessments using a digital cognitive tool, which will take approximately 10–20 minutes to complete. These will occur immediately after each in-lab exercise session in a designated testing space, enabling the study team to capture near-term changes in cognitive function related to exercise. Additionally, participants will complete the full-length digital cognitive assessments at week 0 (baseline) and week 8 in a quiet testing room. These assessments will simulate real-world cognitive tasks and will yield high-resolution, domain-specific cognitive profiles.

Continuous physical activity monitoring

Participants will wear a Fitbit continuously throughout the study, including during both wake and sleep hours. Fitbit-derived data will be categorized into three activity domains:

1)

Protocol-Guided Exercise (PGE): Exercise occurring during supervised, in-lab sessions.

2)

Non-Protocol Physical Activity (NPA): Incidental movement and unsupervised activity outside scheduled sessions.

3)

Total Physical Activity: Combined PGE + NPA, derived from 24-h Fitbit data.

The primary Fitbit metric will be daily step count, a validated proxy for global movement shown to correlate with cognitive, brain, and cardiometabolic health outcomes in older adults [37]. A secondary metric, calories burned, will offer insight into the metabolic intensity of movement. Step count and caloric expenditure will be examined in relation to cognitive function as well as brain and cardiometabolic biomarker outcomes. Analytical models will include PGE and NPA as independent predictors, which will be modeled separately and jointly to assess differential and additive contributions to primary (cognitive, brain, and cardiometabolic markers), secondary (sleep metrics and exercise measures), and tertiary (light exposure and psychosocial measures) outcomes.

Self-reported physical activity

To complement wearable-derived data and assess convergent validity between objective and subjective measures of physical activity, participants will complete two validated, self-report instruments. Specifically, the Physical Activity Scale for the Elderly (PASE; [22]) will be administered at week 0 (baseline) and week 8 (post-intervention). This questionnaire will capture the frequency, duration, and intensity of physical activity over the prior 7 days. In addition, participants will complete the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire, which evaluates the effectiveness of an exercise intervention in community-dwelling older adults. From the CHAMPS questionnaire, a Metabolic Equivalent of Task (CHAMPS–MET) metric will be derived; this metric will be utilized to estimate weekly caloric expenditure [23]. The CHAMPS survey will also be administered at week 0 (baseline) and week 8 (post-intervention). The integration of these two tools will enable a comprehensive triangulation strategy to optimally evaluate alignment and potential discrepancies between perceived and actual physical activity. Discrepancy scores between self-reported and Fitbit data will be computed and examined as potential moderators or mediators of outcomes, particularly in relation to cognitive status and/or adherence.

Biomarker collection strategy

Brain and cardiometabolic health will be assessed using a hybrid biospecimen collection protocol. Two venipuncture-based blood draws will be conducted through Quest Diagnostics, occurring at week 0 (pre-intervention) and week 8 (post-intervention) under standardized fasting conditions. To maximize participant safety and minimize all possible influences of acute exercise [20], pre-intervention blood draws will be obtained no later than 7 days prior to, but no sooner than 24 hours before, the initiation of the first exercise session, and post-intervention blood draws will be obtained within 24–48 hours after completion of the final exercise session. No blood draws will occur on the same day as in-lab exercise. For all participants, plasma samples will be assessed for cardiometabolic risk, which will include high-sensitivity C-reactive protein (hs-CRP), glycated hemoglobin (HbA1c), and fasting total cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides, insulin, and C-peptide levels, which will provide time-sensitive insight into the inflammatory, glycemic, lipid, and insulin resistance markers across the intervention period. Furthermore, the extent of AD-associated neuropathology will be assessed at baseline via plasma samples, which will include amyloid beta peptide 1–42 (Aß1–42), Aß1–40, Aß1–42/Aß1–40 ratio, and phosphorylated tau at threonine 217 (p-tau217). These biomarkers will be subsequently integrated into a single analytical interpretation of AD risk, which has an 88% positive and 91% negative concordance with amyloid-PET-based results [38]. The aforementioned biomarkers will serve as staging and stratification variables, enabling the utilization of such biomarkers as covariates or effect moderators (e.g., assessing whether intervention response differs by baseline pathology status) without presuming measurable longitudinal change over the short intervention window. Additionally, in order to capture biologically meaningful change over an 8-week duration, plasma neurofilament light chain (NfL) will be obtained and measured at baseline and at post-intervention. Unlike the amyloid- or tau-based biomarkers, NfL reflects ongoing neuroaxonal stress and overall neurodegeneration and has demonstrated sensitivity to behavioral and lifestyle interventions, including exercise- and sleep-related alterations, over relatively short time periods (e.g., 8 weeks) [39]. Consequently, NfL is more appropriate for detecting intervention-related biological signals within the timeframe of this pilot study.

Temporal synchronization and data integration

Physical activity, cognitive function, and biomarker data will be aligned using a centralized time-stamped database. Sampling windows will be synchronized with protocol events (e.g., in-lab sessions, assessment points) to ensure precise temporal integration of physiological, cognitive, and behavioral data streams.

Adherence and engagement

In order to assess adherence to the exercise sessions, attendance will be recorded for all in-person sessions, and wearable devices (Fitbit) will track daily physical activity, including steps, heart rate, and durations of physical activity. Weekly check-ins (10–15 minutes) via phone or secure teleconference will be conducted and documented to ensure protocol adherence, troubleshoot technical issues, and maintain engagement. All data will be stored in HIPAA-compliant systems. Fitbit and the Digital Neuro-Signature Platform data will be de-identified and linked using secure participant codes. Statistical models will include age, sex, years of educational attainment, employment status (unemployed/employed), socioeconomic status, baseline sleep metrics, baseline physical activity levels, and cognitive status as covariates. By integrating standardized, in-lab exercises, wearable technology, digital cognitive assessments, and multimodal biomarker data, this arm of the CASE study aims to explore the cognitive, brain, and cardiometabolic impacts induced by structured exercise in aging adults who are at higher risk for AD using a real-world, ecologically valid framework.

Interventional group 2 (sleep only)

Participants randomized to the sleep-only group will participate in an 8-week intervention utilizing the Elemind Neuromodulation headband, an electroencephalography-based, non-invasive, wearable device designed to reduce onset latency through personalized acoustic stimulation that is tailored to the unique brainwaves of each individual (see Fig. 1). This arm is intended to assess the efficacy of a home-based neuromodulation strategy in older adults with varying cognitive and functional baselines.

Fig. 1The alternative text for this image may have been generated using AI.

Elemind Neuromodulation Headband. The wearable Elemind Neuromodulation headband (left) promotes a reduction in sleep onset latency through acoustic stimulation based on each individual’s unique brainwaves (left). The Elemind Neuromodulation headband can be utilized in conjunction with machine learning approaches to optimize personalized treatments. The user-programmed device will use Bluetooth low energy or a direct USB-C connection (right) to control the device and transfer data obtained by the headband to the Elemind application on a smartphone, which will collect sleep metrics

Device use and sleep monitoring

Subjects will start with a 7-day onboarding-screening period, during which participants will wear the Elemind Neuromodulation headband nightly without stimulation to passively establish a baseline sleep pattern and to ensure initial eligibility criteria are satisfied. Following this, the neuromodulation feature will be activated, and participants will be instructed to wear the device at least 3–4 nights per week for 8 weeks. Each use will deliver bone-conduction-based acoustic stimulation tailored to the participant’s real-time brainwave activity. The headband will collect continuous data on multiple sleep metrics, including total sleep time, sleep efficiency, sleep onset latency, restlessness, and time spent in various sleep stages (light (N1/N2), N3, REM). Sleep data will be delivered to the Elemind smartphone application. Raw data will be reviewed regularly for artifacts, such as signal dropout and excessive motion. Nights with incomplete data (e.g., < 4 hours of recording or ≥ 10% missing epochs) will be flagged and excluded from analysis and will prompt follow-up instructions and/or re-onboarding support. The Elemind Neuromodulation device’s sleep staging outputs, while designed to approximate polysomnographic benchmarks, are considered proxies and will be interpreted accordingly. In addition, participants will wear the Lys device continuously throughout the 8-week trial period. The Lys device will measure the intensity, color, and duration of light exposure to gain insights into the relationship between light, sleep, circadian cycles, and energy levels. This device works by communicating with the company’s proprietary app, named Insight, to display light exposure data to the user as well as to provide the individual with goals and insights related to light and health. Additionally, Lys communicates with a separate app, called Collect, which will be used by the researchers to download data at the conclusion of the study. In addition, subjects in this group will also receive Fitbit devices and will be asked to wear the device continuously to passively gauge physical activity levels throughout the trial duration.

Cognitive pulse assessments

Full-length, digital cognitive assessments (approximately 20 minutes) will be conducted at week 0 and week 8 in a quiet testing room at the University of Miami or, if unable to complete in person, via a secure video conference with a trained research assistant or postdoctoral fellow. Throughout the study duration, participants in this group will also complete brief, twice-weekly cognitive pulse assessments in each participant's  own home setting using the Digital Neuro-Signature Platform cognitive tool on two mornings per week after wearing the Elemind Neuromodulation headband the night before.

Biomarker collection strategy

Similar to the first arm, cardiometabolic and brain health will also be assessed using a hybrid biospecimen collection protocol in this arm. Specifically, two venipuncture-based blood draws will be conducted through Quest Diagnostics, occurring during week 0 (pre-intervention) and week 8 (post-intervention) after the final utilization of the Elemind Neuromodulation headband has been completed. Samples will be assessed for hs-CRP and HbA1c levels as well as fasting total cholesterol, HDL, LDL, triglycerides, insulin, and C-peptide levels, which will provide time-sensitive insight into the inflammatory, glycemic, lipid, and insulin resistance markers across the intervention period. Changes in neuroaxonal stress and overall neurodegeneration from baseline will be assessed via plasma NfL levels at weeks 0 and 8. Furthermore, AD-linked neuropathology will be assessed at baseline only via plasma samples, including Aß1–42, Aß1–40, Aß1–42/Aß1–40 ratio, and p-tau217.

Missing data and adherence

Participants missing ≥ 10% of required sleep intervention nights (defined as < 22 nights of wearing the sleep intervention over the 8-week intervention period) will be flagged for sensitivity analyses. If a participant misses > 2 consecutive weeks of data and/or fails to complete either of the full-length, digital cognitive assessments, such participants will be excluded from per-protocol analyses but retained in intention-to-treat models. Multiple imputations will not be applied due to the small sample size; instead, pattern mixture modeling or last observation carried forward (LOCF) methods will be used where applicable.

Adherence to the recommended neuromodulation utilization for the sleep intervention will be monitored via the Elemind application, which will log device usage and track sleep metrics. In addition, weekly phone or video check-ins (10–15 minutes) will be made to monitor engagement, support adherence, and troubleshoot technical issues. All reports of adherence will be documented upon the completion of each call/video check-in.

Limitations

This study will not include a sham stimulation control for the sleep-only group. The decision to forgo a sham condition reflects the real-world, comparative effectiveness design of the CASE study and prioritizes ecological validity over internal blinding. Nonetheless, the absence of participant blinding may introduce potential placebo effects. To address this analytically, expectancy-related influences will be modeled using self-reported perceived benefit measures as an additional covariate in the regression models. Sensitivity analyses will explore whether high expectancy ratings moderate intervention effects. Between-arm comparisons will further contextualize the potential role of non-specific treatment effects in observed outcomes.

In addition, the 8-week interventional period of this clinical trial may not be a sufficient timeframe for detecting significant changes in brain biomarkers; nonetheless, it should be emphasized that the predominant goal of this pilot trial is to identify early trends and signals in these aforestated biomarkers, which will, in turn, inform the design of future, longer-term, fully powered trials. Furthermore, this exploratory approach will enable the assessment of the feasibility and potential effects of each intervention in a relatively small cohort and prefaces more extensive future studies. Notably, the 8-week interventional trial duration was selected based on prior study findings, which showed that behavioral interventions have the capacity to result in early changes in cognitive and physiological measures within a relatively short timeframe [40, 41].

Temporal synchronization

All data sources—including Elemind (sleep), Lys (light exposure), Fitbit (physical activity/exercise), and digital cognitive assessments (cognitive function)—will be time-stamped and aligned using a centralized database. Sampling frames will be linked to specific intervention events and assessment windows to enable a temporally precise integration of cognitive and sleep data streams. By integrating wearable neurotechnology, frequent cognitive assessments, and remote monitoring within a structured intervention framework, this arm of the CASE study aims to evaluate the adherence and early efficacy signals of at-home sleep neuromodulation in aging adults.

Interventional group 3 (combined sleep and exercise)

Participants randomized to the combined intervention group will engage in both structured exercise sessions and sleep neuromodulation over an 8-week study period. This arm is designed to explore the additive and potentially synergistic effects of engaging in both interventions concurrently while assessing adherence and participant burden, which will, in turn, inform future multimodal approaches to cognitive aging and AD prevention.

Protocol structure and considerations

To reduce participant burden and improve standardization, in-lab exercise sessions and cognitive assessments will follow the same cadence and structure as in the exercise-only arm: twice-weekly, 60-minute, supervised sessions that will focus on aerobic and resistance training, home-based walking program, and brief digital cognitive assessments (the Digital Neuro-Signature Platform) immediately after each session. Participants will also wear the Elemind Neuromodulation headband for at least 3–4 nights per week across the 8-week period, with an initial 7-day, passive, onboarding screening phase of wearing the headband nightly without stimulation in combination with wearing the Fitbit device continuously to establish baseline sleep patterns, physical activity levels, and ensure that all eligibility criteria are satisfied. Finally, subjects will also wear the Lys device continuously throughout the 8-week trial period.

To manage cumulative burden, scheduling flexibility will be emphasized. Although participants will be offered a choice of days and times for in-lab sessions to fit each participant’s weekly routines, morning times will be strongly encouraged across all participants, as prior work has suggested that older adults generally show better cognitive and exercise performance in the mornings [42, 43]; this will further improve standardization. Staff will work closely with participants to accommodate visit times and ensure ample time for recovery between activities. Weekly adherence and well-being check-ins will be conducted and documented to monitor fatigue, motivation, and adverse effects.

Cognitive pulse assessments

As in the other arms, participants will complete brief, digital cognitive assessments biweekly during lab visits and full-length assessments at week 0 and week 8. For improved standardization, participants in this group will also be asked to attend in-person exercise sessions on the days after they wore the Elemind Neuromodulation headband the preceding night.

Biomarker collection strategy

Biomarker collection through Quest Diagnostics (venipuncture at week 0 and week 8) will be conducted following the aforementioned procedures, with attention to minimizing scheduling conflicts with intervention activities. Just as in the exercise-only intervention, pre-intervention blood draws for this arm will occur no sooner than 24 hours before but no later than 7 days prior to commencing with the initial exercise session. Additionally, post-intervention blood draws will be obtained within 24–48 hours after completion of the final exercise session. No blood draws will occur on the same day as a scheduled exercise session.

Analysis strategy

This arm enables a unique opportunity to assess both the independent and combined contributions of sleep and exercise to cognitive, brain, and cardiometabolic outcomes. Statistical models will include main effects for sleep (e.g., adherence to Elemind usage), exercise (e.g., PGE, NPA), and interaction terms to evaluate additive or synergistic effects. Dose-response relationships will be explored using adherence metrics and physiological markers (e.g., heart rate during exercise, sleep efficiency). Adherence to both modalities will be assessed as previously described, summarized descriptively, and modeled as predictors in multivariable analyses of primary outcomes.

Compensation and parking reimbursement

All participants will receive $50 at baseline (week 0) and $50 at the conclusion (week 8) visit, totaling up to $100 for full participation in the trial. Participants will be issued a reloadable debit card (ClinCard) that can be used for study-based compensation at the University of Miami. Funds will be loaded onto the card according to the payment schedule. The study staff will provide information about how the card works. The company administering the card will require a full name, address, and date of birth to be entered online for payment. This information will only be used for payment and communication purposes and will not be given to another company or linked to any of the study data. All prospective participants who pass pre-screening eligibility but are found to be ineligible after the initial 7-day onboarding screening period and are also not eligible for or interested in being reassigned to an alternative intervention group for which they may be eligible will not be invited for further participation but will receive $20 compensation for their efforts via a ClinCard debit card. Furthermore, for all in-person visits, participants will be reimbursed for either parking or via Metro passes at the conclusion of each in-person visit.

Measures and instruments

To capture a comprehensive and multidimensional view of participants’ cognitive, emotional, behavioral, and physiological profiles, the study will employ both survey-based instruments and digital device-based measures. Instruments will be categorized into predictor and outcome variables and will span psychosocial, cognitive, behavioral, and biological domains.

Self-report surveys will be administered at baseline (week 0) and at the 8-week follow-up by a trained research assistant or postdoctoral scholar via in-person visits or, if unable to come in person in the sleep-only group, by a secure video conference. These will include the PASE [22] and CHAMPS [23] questionnaires to assess physical activity and weekly caloric expenditure, respectively, for those in the exercise-only or sleep + exercise interventions. Additionally, each participant will complete all validated Patient-Reported Outcomes Measurement Information System (PROMIS) short-form questionnaires that measure sleep disturbance, self-reported cognitive functioning, emotional support, depression, anxiety, life satisfaction, and social isolation [21] at the baseline and post-intervention visits, except for the General PROMIS Life Satisfaction 5a questionnaire, which will be completed at the baseline visit only. Additional measures will include a Demographic Questionnaire, a Chronic Health Questionnaire, and the Cross Ethnic-Racial Identity Scale [44] to capture relevant sociodemographic and psychosocial predictors (see Table 3). Objective data will be collected via