Study design

LETHE (ClinicalTrials.gov NCT05565170) is a two-year pilot RCT conducted at four European sites: Medical University of Vienna (Austria), Finnish Institute for Health and Welfare (Finland), University of Perugia (Italy), and Karolinska Institutet (Sweden). At each site, eligible participants were randomized in a 1:1 ratio in blocks of four (centralized computer-based allocation performed by project partner FH Joanneum) to either a 1) structured digitally supported multimodal lifestyle program (= intervention; scheduled program designed and led by professionals) or 2) a self-guided multimodal lifestyle program (= control; regular health advice).

The structured LETHE intervention follows a hybrid approach where in-person intervention activities (on-site and remote; adopted from the original FINGER program) are supported by independent activities in the Android smartphone application designed by the LETHE Consortium (the LETHE App). The LETHE App includes personalized features and dynamic content supporting engagement in the lifestyle program and risk factor self-management. The self-guided group is encouraged to implement general health/lifestyle advice independently; this group has access to a simplified version (view) of the LETHE App including educational material selected by the study teams but no personalized content. All participants have the possibility to contact the study staff throughout the study, and they also receive support from so-called digital coaches (dedicated study staff members) who help with any technical questions and problems in person or by email/phone.

Like in FINGER, blinding is pursued such that cognitive outcome evaluators are blinded to randomization and not involved in the intervention. Group allocation is not actively disclosed to participants. The main study visits, including clinical and cognitive assessments, take place at baseline and at 6, 12, and 24 months; additional data are collected digitally (actively via outcome-related questionnaires in the LETHE App and passively via monitoring through smart devices). During the second year, a subset of intervention group participants will be invited to join a two-month sub-study exploring novel interactive technology and its feasibility in the context of the LETHE intervention (audio smart glasses paired with a voice interaction app, a social robot). The overview of the study is presented in Fig. 1.

Fig. 1

Overview of the LETHE trial design

Participants

Participants were recruited using a local social media (Facebook) advertisement in Sweden, Finland, and Austria. In Italy, local associations for older people were utilized, as well as printed posters which were distributed in the hospital/memory clinic. The study population in LETHE is similar as in FINGER: older adults (age 60–77 years) at risk of dementia based on the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) Dementia risk score [21] and cognitive performance, but without any substantial cognitive impairment. LETHE participants were additionally required to have sufficient digital readiness to follow the intervention. The full inclusion and exclusion criteria are shown in Table 1.

Table 1 Participant inclusion and exclusion criteriaStudy procedures and data collection

During recruitment, individuals expressing their interest to join the study were first pre-screened over the phone to check basic inclusion criteria to reduce screening failures (age, digital readiness/skills, and CAIDE score). Digital readiness was assessed by interviewing the participant about their prior use of digital devices (which device, how often and for which purposes, and if the participant is comfortable with using Internet and email (e.g., search for information online, read and send emails)), about their current internet access, and willingness to use a phone that is compatible with the LETHE App. Potentially eligible persons were invited to full screening for detailed eligibility assessment, including cognitive testing and interview to confirm absence of medical exclusion criteria (Table 1). Screening was conducted on-site (Austria, Italy, Sweden) or online (Finland).

At baseline, in addition to conducting clinical, cognitive, and other assessments, the study staff installed the LETHE App on participants’ smartphones (a new smartphone was provided if participant’s existing phone was not compatible with the technical requirements of LETHE). Participants were requested to complete a set of questionnaires (e.g., lifestyle-related) in the App within two weeks from the baseline visit. Once completed, participants were randomized, and the full version of the App was activated (different view and content for the intervention and control groups). Successively, an extra visit with the digital coach was arranged to introduce the entire App content to the participants, and to hand out a smartwatch (intervention group: Fitbit Sense; control group: Fitbit Charge 5) and a tablet computer for those intervention group participants who did not yet own one.

After baseline, the main study visits take place at 6, 12, and 24 months, to collect clinical and cognitive outcome data. At these timepoints, participants in both groups also complete outcome-related questionnaires in the LETHE App. Other digital data collection takes place continuously throughout the trial, i.e., passive monitoring through the phone, LETHE App, and smartwatch. Table 2 summarizes the data collected at different timepoints. The trial also includes biomarker studies: at baseline and end of study, blood samples are collected for e.g. analysis of Alzheimer’s disease (AD) blood markers and MRI is conducted (in a subsample) across all sites.

Table 2 Overview of assessments conducted for all participantsOutcome assessmentsPrimary outcomes

The primary outcomes are: 1) feasibility of the digitally supported multimodal lifestyle intervention and 2) change in dementia risk based on validated risk scores.

Feasibility is assessed based on retention rate (proportion of randomized participants completing the trial in each group) and adherence to the intervention. A retention of 65% (max. 35% drop-out) is considered successful. Reasons for discontinuation are recorded. In terms of adherence, both digital and non-digital intervention activities will be considered. The following will be assessed: usage of and engagement with the LETHE App and smartwatch (e.g., frequency and duration of logins, wear time), and participation in study visits and intervention-related activities/meetings. Feasibility is further explored by investigating participants’ opinions on the intervention and the usability of the LETHE App / digital tools (quantitative assessment with the System Usability Scale [22] and qualitative interviews in a subsample).

Change in dementia risk is assessed based on two scales, CAIDE [21] and LIfestyle for BRAin health (LIBRA) index [23]. Both are validated tools to estimate risk of late-life dementia [24, 25], and findings from FINGER suggest that they can be useful in quantifying risk reduction and prevention potential in an at-risk population and trial context [8, 9]. CAIDE considers non-modifiable and modifiable risk factors: age, education, sex, systolic blood pressure (BP), body mass index (BMI), total cholesterol, and physical activity. Total score is the sum of the points assigned for each factor (range 0–15; higher scores indicate higher risk). LIBRA consists of a weighted sum score of modifiable risk and protective factors; factors in the original version include coronary heart disease, diabetes, hypercholesterolemia, hypertension, depression, obesity, smoking, physical activity, renal disease, alcohol use, cognitive activity, and diet (theoretical range from –5.9 to + 12.7; higher scores indicate higher risk).

Secondary outcomes

Secondary outcomes include changes in lifestyle/adherence to healthy lifestyle, stress-related symptoms, sleep problems, health-related quality of life, health literacy, and cognition (composite z-score of 14 tests in the extended Neuropsychological Test Battery, NTB [26], adapted from the FINGER [6] and MET-FINGER [27] RCTs). The assessment methods and scales are summarized in Table 3.

Table 3 Methods and scales to assess secondary outcomesExploratory/other outcomes

Exploratory outcomes include changes in individual lifestyle domains and risk factors, mood/depressive symptoms, sleep quality/duration, physical performance, and cognitive and functional measures. Changes in AD/dementia-related biomarkers will also be explored. The assessment methods and scales are summarized in Table 4.

Table 4 Methods and scales to assess exploratory/other outcomesInterventionStructured multimodal lifestyle program (intervention group)

The LETHE intervention is a digitally supported, structured multimodal lifestyle program delivered partly in-person and partly digitally using the LETHE App and other digital tools (tablet, smartwatch). The intervention domains are 1) Dietary guidance, 2) Physical activity, 3) Cognitive training, 4) Monitoring and management of vascular and metabolic risk factors, 5) Social stimulation, and 6) Sleep and stress management (only digital). The in-person intervention activities are organized both face-to-face and remotely as online meetings. The activities are aligned with the original FINGER and the more recent FINGER-based RCTs [27, 28].

The design and development of the multimodal lifestyle intervention program are centrally coordinated and harmonized. The intervention activities at the four sites share common key principles and similar schedules to ensure comparable intervention content and intensity. Detailed staff manuals guarantee harmonized intervention delivery across all study sites. Certain local adaptations, as well as tailoring to individual participant needs are nevertheless allowed to optimize feasibility and efficacy. Also, each site designs the detailed intervention delivery (e.g., balance between face-to-face and online meetings) depending on local arrangements and feasibility, as well as participant preferences.

To support adherence, the different intervention domains were introduced gradually during the first six months of the trial, starting with individual vascular risk factor and dietary consultations which were followed by cognitive and finally exercise group sessions. Participants gained access to all the intervention content in the LETHE App directly after randomization and the digital introduction visit.

Dietary guidance

The dietary intervention aligns closely with the principles of FINGER [29] and is based on general dietary recommendations with special attention on nutritional issues common among older adults. Local adjustments are allowed to align with national dietary recommendations. The key dietary intervention goals in nutrient and food intake levels are summarized in Supplementary Table 1 (Additional file 1). The intervention is delivered through individual consultations (1–2 sessions, approx. 30–45 min each) and small group sessions (3–4 sessions, approx. 45–60 min each) with a trained nutritionist. Individual consultations include a thorough assessment of the participant’s current dietary habits and provide tailored, practical advice on how to improve diet and implement changes in daily routines. All recommendations are adjusted according to individual needs considering e.g., health status and weight. Group sessions provide more information and support the implementation of relevant dietary changes. Group support is exploited through joint discussions. Participants are encouraged to invite their spouse/partner to join the sessions.

Physical activity

The physical activity intervention is based on FINGER and the international guidelines for older adults [30]. The program combines aerobic, strength, and balance training, with progressively increasing intensity and frequency. It is tailored to meet individual needs, e.g., fitness level, health status, and personal preferences. The goal is to make permanent changes to include physical activity into everyday life. Participants are encouraged to lead a more active and less sedentary life and provided with practical advice on how to incorporate activity in their daily routines.

The exercise program is led by a physiotherapist or trained professional experienced in working with older adults, and consists of the following components: an initial motivational consultation and muscle strength testing to define the optimal training load; group sessions on strength training (at least one weekly 30–60 min session at the gym and/or online); and independent aerobic exercise (planned together with the professional based on participants’ needs and preferences). The progression pattern for the training is shown in Supplementary Table 2 (Additional file 1). Participants are advised to use the on-demand video material in the LETHE App to reach the goal of two weekly strength training sessions. To track their activities and self-monitor exertion level to ensure right intensity level, participants are encouraged to utilize their smartwatches.

Group sessions on strength training follow a similar structure and concept regardless of whether they take place on-site or online (e.g., duration, targeted muscle groups). Remote sessions rely on bodyweight exercises, resistance bands, and exercises utilizing everyday tools at home (e.g., chairs, bottles). Even if most group sessions were remote, all sites organize a few on-site sessions at the beginning and end of the intervention, as well as in-between, to ensure safety and proper exercise techniques, and to facilitate grouping, support motivation, and monitor progression.

Cognitive training

The cognitive intervention is delivered through group sessions (3 sessions, approx. 60 min each) with a psychologist or other trained professional, and independent cognitive training with a web application available via the LETHE App (cTRAIN, provided by Combinostics Ltd and adapted from the program used in FINGER [31]). The group session topics are cognitive abilities, aging-related changes in cognition, brain plasticity, factors affecting cognition (e.g., sleep, stress, mood), and tips to stay mentally fit. The first group session is dedicated to introducing the cTRAIN program; after that the participants have access to the program for the whole trial duration. cTRAIN includes six games to train working memory (visuo-spatial span task), executive functions (two working memory updating tasks, spatial and verbal), mental speed (set-shifting task), and episodic memory (word associate task i.e., word triplets and a classic memory-game). The software introduces automatically different tasks in a sequential order (two games available at a time for each two-week period). With improving performance, the difficulty of the games increases, and more advanced levels are unlocked. Participants are recommended to train three times per week for 10–15 min/session, but they can train more if they wish. Activity and performance are registered automatically, and participants can monitor selected statistics (completed sessions, high scores).

Monitoring and management of vascular/metabolic risk factors

Risk factor monitoring and management is based on country-specific evidence-based guidelines. The goal is to identify risk factors and motivate participants to take action by giving tailored, targeted counselling and personalized feedback taking into account individual situation and motivation. Risk factors/conditions to cover include BP/hypertension, dyslipidemia, diabetes/ glucose levels, smoking, alcohol consumption, weight management (acknowledging the complex role of weight changes in old age and risk of frailty/malnutrition), and other relevant lifestyle factors. The intervention includes 1–2 individual consultations with a nurse and physician, respectively (in total 2–4 sessions, approx. 45–60 min each). Extra measurements of e.g., BP or waist circumference can be conducted to support the consultation. If medication initiation or adjustment is needed, the study physician writes a prescription, or the participant is recommended to contact (or referred to) the regular health care provider.

Social stimulation

In previous multimodal prevention RCTs, social engagement was crucial to support motivation and intervention adherence [10, 32]. In LETHE, social activities are therefore strongly supported and stimulated through regular group meetings. Group sessions are designed to facilitate open discussions and social interaction among participants. This interaction is also encouraged outside the scheduled sessions, e.g., via local WhatsApp group chats.

Sleep and stress management

Stress and sleep are acknowledged as relevant factors for brain health, although more evidence is needed of their potential causal role as risk factors [33, 34]. Stress and sleep problems can nevertheless interfere with health as a whole and prevent from making sustained lifestyle changes. No separate in-person activities are organized in this domain, but the topics are addressed as part of other consultations as applicable. Participants can independently monitor sleep with the smartwatch and access relaxation videos in the LETHE App.

Self-guided multimodal lifestyle program (control group)

Participants in the control group are advised to build their own healthy lifestyle program based on the standard advice they receive at the main study visits and through the simplified LETHE App. Participants are encouraged to independently implement relevant changes in their daily routine. The simplified LETHE App includes a library of educational material selected by the local study teams, but none of the personalized features or notifications (see next section and Fig. 1). The smartwatch worn by the control group is a simpler model than the one worn by the intervention group (serves mostly passive data collection, yet allows e.g. physical activity tracking). Like the intervention group, the control group receives the results of routine blood tests (e.g., lipids), information about their meaning, and if needed, advice to seek medical care.

LETHE App

Given the lack of existing apps that are appropriate for the LETHE target group and aligned with the principles of the FINGER intervention model, a new app was in the project to support the intervention delivery and trial data collection. The LETHE App is an Android native app; the development process and technical implementation are described elsewhere (Hilberger et al., in preparation). In brief, the LETHE App features two different views (full view with all functionalities for the intervention group; simplified view with selected functionalities for the control group). Figure 2 shows the two different overviews (dashboards) of the LETHE App. All content is available in English and the four trial languages (Finnish, German, Italian, Swedish). Translations were provided and checked by the local study teams.

Fig. 2

Overview (front page) of the different LETHE App views (full view for the intervention group, simplified view for the control group)

The key features of the LETHE App are summarized in Fig. 1. Features for both study groups include: a calendar (to view and keep track of study appointments and join online meetings if applicable), questionnaires (for outcome-related assessments at timepoints shown in Table 2), option to record current mood (by selecting emoticons), and a library of educational content covering all domains of the lifestyle program (external websites). This material was selected by the study teams to ensure it is appropriate for this target group, evidence-based, reliable, and aligned with the principles of the lifestyle intervention as well as local guidelines. The full App includes several additional features designed to support the delivery of the multimodal lifestyle intervention and encourage independent engagement in healthy activities. Some of the features and activities can be viewed and modified by the study staff on a web portal (LETHE Clinical Trial Management System, CTMS) which helps deliver the intervention in a more personalized way.

For diet, a short questionnaire is available in the App for simple self-monitoring of healthy diet adherence (e.g., consumption of fish, processed meat, and fruit and vegetables). The questionnaire is divided into three blocks, each of which appears weekly (Additional file 1, Supplementary Table 3). For physical activity, on-demand exercise videos focusing on strength and balance training are available (selected or filmed by the local study teams to accommodate different fitness levels). These videos complement the in-person group sessions. To relax or help fall asleep, YouTube videos with soothing melodies and breathing exercises are available (selected by the study teams). For cognitive training, participants have access to the cTRAIN program through the LETHE App. cTRAIN, as well as all videos in the LETHE App, can also be opened on a tablet or computer, by scanning a QR code or sending the link by e-mail. For social stimulation, participants are offered the possibility to connect with each other in a local WhatsApp group chat. For vascular risk factor control, the App includes a diary for self-monitoring of smoking, alcohol consumption, and BP. The professionals can view the entries in the CTMS, and results can be discussed at the individual consultations.

The full LETHE App also includes a feature for personal goals. The goals are discussed and set together with the professional to ensure they are relevant and follow the SMART principles (specific, measurable, achievable, realistic, time-bound). Goals are displayed in the App as items on a to-do list, and they can be ticked off once reached. The full App also includes a library of practical everyday tips and behavioral suggestions to help individuals implement healthy habits into the daily routine (so called tiny habits, based on habit formation theory [35, 36]). The library was originally created for a large Finnish type 2 diabetes online prevention RCT [37] (library publicly available in Finnish under CC BY 4.0 license [38]). Lifestyle domains covered were diet, exercise and sedentary lifestyle, mental wellbeing, sleep, smoking, and social interaction. For LETHE, the library was reviewed, translated, and partly adapted and expanded by the study teams to ensure appropriateness for our context. For example, the dietary and exercise advice was aligned with the principles of FINGER, and a new section was developed for cognitive stimulation. Participants can choose new habits and unselect old ones as often as they wish (total number of available habits > 500; examples in Additional file 1, Supplementary Table 4). Participants can indicate regularly if the habits were successfully implemented or not. Finally, a feature for personalized semi-automated feedback is currently under development. Based on data from the smart devices, motivational feedback messages will be sent, and a weekly performance/adherence score will be calculated and shown in the App (Fig. 2).

Exploring novel interactive technology (sub-study)

A subset of intervention group participants will be invited to test novel interactive technology as a complementary way to engage with the LETHE App. Two different technologies are tested: a social robot (Temi) and audio smart glasses (FAUNA Spiro) (Fig. 1). The robot can navigate around the house and display LETHE App content on a touch display. It can also assist by reminding about intervention-related tasks. The audio glasses have a Bluetooth microphone and headphones. In combination with a voice interaction app, glasses enable hands-free interaction with the LETHE App functionalities. Instead of reading on the screen and typing answers to questions as done with the smartphone, participants can listen to App contents and enter information through voice interaction. Both devices are CE-certified.

Statistical considerations

LETHE is an RCT assessing primarily feasibility. In line with CONSORT extension guidelines for such RCTs [39], no formal sample size calculations were conducted. Sample size is in line with other feasibility RCTs testing multimodal preventive lifestyle interventions in similar populations [28, 40,41,42], and many ongoing studies assessing digital brain health interventions [43]. The two study groups will be compared to assess differences in the trial outcomes, as applicable.

Ethical and safety aspects

Trial was approved by local ethical committees in all four countries. All participants provided a written informed consent prior to enrollment. Separate consents were obtained for screening and the full trial; an additional consent will be obtained for the sub-study. A verbal informed consent was allowed for remote screening. Participants’ study partners/informants provided their own consent (involving a partner e.g., family member is recommended but not mandatory).

The multimodal lifestyle intervention is not expected to cause harm or involve major health risks [6]. No interim safety analysis is therefore planned. Information about adverse events is collected at the study visits and with a brief digital questionnaire every three months. All participants are informed about the results of their routine health examinations, blood tests, and any other relevant findings concerning their health. If needed, participants are either referred to medical care or advised to contact their regular health care provider. Participants are covered by local insurance.

Data protection and privacy

All study documentation collected at the sites is stored securely in local premises, labeled with a unique participant ID, and kept apart from identifying information. All data collected via the LETHE App, CTMS (including electronic case report forms), smartwatch, and phone sensors are stored on a secure cloud-based server with restricted access (hosted by EGI Foundation in the Netherlands). In addition to the participant ID, participants have unique dummy Google accounts to login the LETHE App and the other web applications used in the RCT (e.g., cognitive training program). Dummy accounts enable the linkage of data from different sources on the server. After the end of the LETHE project, data are transferred to the study sites and stored locally. Third parties e.g., Fitbit, collect and process certain data for their own purposes via their products (e.g., usage of smartwatch and related app); this is explained to the participants in the informed consent form. Third parties do not have access to the trial data.

Public involvement

An Advisory Board (AB) including members of the public with an interest in or affected by cognitive impairment was set up at the beginning of the project (work led by Alzheimer Europe in collaboration with other partners). The AB consists of seven members from Austria, Finland, Italy, and Sweden. The AB has provided feedback on the trial design and intervention concept, participant materials, digital devices, and issues concerning recruitment, ethical aspects, and data protection. The AB contribution is described in detail elsewhere (Rosenberg et al., in preparation).