REMINDER program: a randomized controlled trial protocol of a neuropsychological intervention for lifestyle modification in older adults at risk of dementia

doi:10.21203/rs.3.rs-5303358/v1

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REMINDER program: a randomized controlled trial protocol of a neuropsychological intervention for lifestyle modification in older adults at risk of dementia

https://doi.org/10.21203/rs.3.rs-5303358/v1

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Background

Most dementia risk reduction trials encompass interventions mostly focused in cognitive and health monitoring risk factors, with less focus is given to psychosocial risk factors (e.g. social isolation, depression, anxiety) which can contribute to impoverished engagement in brain protective lifestyles. The REMINDER program was designed to increase at-risk older adults’ competence in terms of cognitive reserve, socialization and emotion regulation skills and goal setting/goal-monitoring; within the framework of the dementia prevention available guidelines.

Aims

This manuscript aim is to present the protocol for two randomized controlled trials for the validation of the REMINDER program.

Methods

The REMINDER study will a Community Trial (cognitively unimpaired older adults at risk; N = 270) and a Clinical Trial (individuals with Mild Cognitive Impairment; N = 270). The Clinical Trial will include an additional harm that combines caregivers’ education and support with the REMINDER program. Participants will take part of the REMINDER program for 20 sessions and complete pre/post and follow-up outcome assessment measures. This neuropsychologist-led group program include education, experiential/reflective and practice moments, including behavior modification techniques throughout the modules. Primary outcomes will be a cognitive function and healthy lifestyle behavior. Secondary outcomes include performance in specific cognitive functions, functional status, psychosocial/mental health indicators and blood-based markers of neurodegeneration.

Conclusions

Part of the World-Wide FINGERS network, the REMINDER program aims to contribute with the inclusion of goal monitoring, emotion regulation techniques, peer support and other behavioral techniques in a dementia prevention trial, fostering engagement and long-term adherence to protective lifestyles across the dementia risk continuum.

Trial registration

ClinicalTrial.gov Identifier NCT05296980

psychosocial risk factors

dementia prevention

older adults

mild cognitive impairment

brain health skills

Background and rationale

People living with dementia and mild cognitive impairment may face significant impact in their well-being, the ability of daily living activities and social functioning [1]. The prevalence of dementia is rising, posing a significant public health burden. Globally, affects over 50 million people worldwide [2]. This number is projected to triple by 2050, particularly in low- and middle-income countries, with substantial economic and social costs [3]. In Portugal, around 6% of individuals with 60 or more years old have one type of dementia, and this percentage tends to increase to 9% by 2037, with Alzheimer’s Disease representing 70% of these cases [4, 5]. In the meantime, interventions determined to prevent and/or delay the onset of dementia and the elimination, reduced exposure to, and/or a better management of several common modifiable risk factors, have been developed with the purpose to potentially prevent around a third of all dementia cases [6, 7]. In fact, despite the absence of a cure, evidence suggests that 45% of dementia cases are attributable to modifiable risk factors (low education in early life and low cognitive reserve, hearing loss, high LDL cholesterol, traumatic brain injury, hypertension, obesity, excessive alcohol consumption in midlife, diabetes mellitus, depression/stress, physical inactivity, smoking, social isolation, visual loss, and exposure to air pollution in later life), altogether presenting a crucial opportunity for prevention [8]. Within these factors, one can identify some psychosocial risk factors like stress, social isolation, and depression, which are impactful factors for individuals’ mental health [9].

Promising multidimensional interventions, like the FINGER trial – Finish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, demonstrate the potential to reduce dementia risk [10, 11]. This was the first large multidomain randomized controlled trial (RCT), with 1259 individuals and longitudinal RCT, two years. To date, results demonstrated that a multidomain intervention, including diet, exercise, cognitive training, and monitoring vascular risk, can improve or maintain cognitive functioning in older people from the general population at risk of dementia [11]. Other multidomain interventions have been targeting factors as diet, exercise, cognitive training, and vascular risk [12, 11, 13]. However, there are several scientific gaps that hinder a wider and more effective implementation of dementia risk reduction (DRR) programs in large scale and with diverse populations. On one side, drop-out rates in some of the FINGER-like trials exceeded 35%, highlighting the need for approaches to increase engagement and adherence, and the need for disentangling the reasons for low adherence to these programs [14, 15]. On the other side, existing interventions, at least those providing clear information in research papers regarding the program contents and structure, often tend to prioritize physical and cognitive interventions, neglecting psychosocial factors, despite their both significant contribution to dementia risk and their impact on decreased engagement to health interventions in general. Finally, most of the available studies exploring the efficacy of dementia prevention programs focus only on healthy older adults or older adults with a significant number of co-occurring modifiable and non-modifiable risk factors, while those with Mild Cognitive Impairment (MCI) are at a particularly higher risk of developing dementia and are relatively underrepresented in intervention studies [16]. In fact, this pre-clinical stage of dementia is a clinical group, increasingly conveniently followed in clinical settings with efforts in early diagnosis and monitoring, but there is a lack of focus on preventive interventions for this group at the highest risk of developing dementia (the annual rate of conversion between MCI and Alzheimer’s rounds 10 to 15%) [17]. Recent research demonstrates the value of multidimensional interventions to prevent cognitive deterioration and ameliorate overall functioning and well-being, particularly if it enrolls also the caregivers with psychoeducation approaches [18-20].

Randomized controlled trials (RCT) in the prevention of dementia provide the highest level of evidence to evaluate change after a program aimed to reduce dementia risk, however, it is challenging to conduct such studies in this field, especially due to duration of the interventions and also to population heterogeneity [6, 21, 22]. Nonetheless, so far, the existing interventions have mainly evaluated the effects on global cognition or on specific domains [12, 23, 11, 13], as well as in the incidence of dementia, which is an outcome with poor reliability regarding the length of the studies and the time for conversion expected in at-risk populations. However, besides cognition, these interventions should be directed to lifestyle changes to reduce modifiable dementia risk, therefore being necessary to assess whether individuals participating in DRR trials effectively adopt a more protective lifestyle for their brain and global health [24]. However, to our knowledge, most DRR trials have not examined lifestyle and behaviour change as part of their main outcomes, which has been stated to be critical to long-term health indicators [25].

In the face of the current opportunities and challenges brought by the existing dementia prevention trials, most belonging to the World-Wide FINGERS network [26], we developed a group-based multidomain neuropsychological program with a 10-week – named REMINDER – aimed to promote healthy lifestyles by empowering brain and mental health in tandem. Preliminary findings from a pilot feasibility trial [27] with forty community-dwelling at-risk individuals are encouraging with 95% adherence and reliable change in lifestyle habits. However, despite these results potentially promising, further validation is needed, and using an RCT, we aim to assess REMINDER’s efficacy in a larger randomized sample. Thus, we developed a protocol to evaluate this program's efficacy in both community-dwelling individuals aged 60 years or older and those diagnosed with Mild Cognitive Impairment (MCI), a population at a higher risk of conversion to dementia. Following recent studies involving brain health programs for MCI patients [19], we aim to test the REMINDER program value both in community and clinical settings, following the potential continuum of cognitive impairment prior to dementia, with the purpose to prevent or delay its clinical onset.

Given that the REMINDER program will be primarily tested in Portugal, to our knowledge, it will be the first dementia prevention trial to be tested in our country. This will consider the specificities of the Portuguese-aged populations (low levels of education, a significant number of regions with low to very low population density, etc.) that could enable the transfer of these findings to other comparable cultural/contextual realities.

Objectives

Therefore, our aims are:

To test the efficacy of the REMINDER program for improving cognition and protective lifestyles in individuals at risk of dementia (community-dwelling or MCI) at short and medium term;
To examine the efficacy of the REMINDER program in neuropsychological function (emotional, cognitive, and functional);
To examine the additive effect of including the REMINDER4Carers to the REMINDER program in lifestyle behaviour, cognition, and well-being of MCI patients;
To examine the effects of the REMINDER program on markers of neurodegeneration (blood-based biomarkers and neuroimaging markers).

We hypothesize that REMINDER participants will exhibit significant and sustained positive changes in lifestyle behaviors (e.g., improved physical activity, healthier diet, meaningful social interactions, sleep hygiene, cognitive stimulant activities, and frequent health monitoring) and global cognition, compared to the waitlist control group. We hypothesize that more positive outcomes are expected for the REMINDER group but not for the control. For a subset of MCI participants, we will offer an additional condition involving the patient’s partner's participation in REMINDER. We hypothesize that this complementary support (named REMINDER4Carers) will lead to improvement in the primary outcome compared to REMINDER alone, according to previous literature stating care partners as relevant actors to be involved in behavioral change interventions [18, 20]. We anticipate positive impacts in secondary psychosocial and cognitive aims as well.

Trials design

The study will assess the program's efficacy in healthy at-risk individuals and those with Mild Cognitive Impairment (MCI) across community and clinical settings. For answering our research questions, this project employs two superiority randomized controlled trials (RCTs) running in parallel. The Community Trial targets at-risk healthy individuals (N=200) and will be a two (1:1) arms single-blind randomized controlled trial: 1) REMINDER protocol and 2) waiting list control group without active intervention. The Clinical Trial targets individuals with MCI (N=150) and will be a three-arm RCT with 1:1:1 randomization to REMINDER alone, REMINDER and caregiver, or waitlist.

Participants, interventions, and outcomes

Study setting

This project will take place in both rural and urban centres in Portugal. In this region, health services constraints (e.g., lack of primary care doctors for all users, lack of physical settings to provide prevention interventions) and an economic and political crisis have led to underfunding for health prevention proposals. This has disrupted the continuity of support for the current project, despite the increasing adherence of research and clinical partners to the project. We will utilize established relationships with key stakeholders for effective outreach and dissemination: 1) At-risk older adults in community settings (reinforce prior collaborations with established associations of older adults, partner with city councils, and recruit through social media and public awareness campaigns); 2) Clinical (reinforce and formalize partnerships with key healthcare providers in targeted clinical units).

Eligibility criteria

Participants or their representatives must give written, informed consent before initiating any study procedures (see Appendix 1 for Informed Consent Form).

Inclusion criteria

Individuals between 60 and 80 years old, inclusively, with a dementia Risk Score of +2 (according to the LIBRA score) [28]; meeting one of the adapted CERAD criteria for very mild cognitive impairment [i) MMSE between 21 and 28 points, ii) memory learning task (3x16 words) of 25 words or less, iii) delayed recall: 75% or less]; with elementary reading and writing skills; with access to the internet at least two times per week; with basic digital literacy skills or with a close relative able to provide access to videoconferencing, will be eligible to participate in this study. For the clinical population (MCI), a clinical diagnosis of MCI as defined by the National Institute on Aging-Alzheimer's Association workgroups - NIA-AA [29] will be an additional inclusion criterion for this group, as well as the availability of the caregiver (who should live or spend at least 10 hours a week with the person) to participate in the study.

Exclusion criteria

Exclusion criteria for both trials will include a history of neurological or psychiatric conditions likely to affect cognition; sensory deficits or mobility limitations preventing the effective delivery of the assessment or intervention; significant functional deficits; or a diagnosis of dementia.

Interventions

The REMINDER intervention

The REMINDER protocol was developed based on the existing contents of FINGER-like trials (psychoeducation, cognitive training, physical and nutritional advice), culturally adapted cognitive intervention materials [30], and behaviour change techniques focused on increasing engagement and decreasing the impact of psychosocial risk factors.

The REMINDER intervention combines 20 group sessions (with an approximate length of 60-75 min) twice weekly over 10 weeks. The content of sessions will integrate brain health psychoeducation, cognitive training, the practice of compensatory memory aids, personally meaningful goals management training, and stress management techniques (Table 1 details REMINDER sessions contents). Specifically, a set of contents and structures were designed to address existing gaps in the literature. Namely, to overcome low adherence, the program includes interactive and personalized sessions, including strategies like goal setting and mindfulness drawing from previous work with these populations [30, 31], as well as motivational strategies (motivational interviewing, positive reinforcement, and progress tracking) to encourage adherence. In addition, to target specifically the psychosocial risk factors (stress, social isolation, depression, among others) [32], we incorporated stress management techniques based on scripts from compassion-based therapies as well as relaxation techniques [33, 34], social interaction and support and emotion regulation strategies (e.g. attention deployment, positive cognitive reappraisal, reframing speech training). Believing that merging the brain, these behavioural strategies in a dementia risk reduction program will foster individuals’ mental health and build their capacity to draw on improved psychological and cognitive reserve to prevent and cope with remaining risk factors.

A manualized protocol was built to offer enough standardized elements and guidelines for the program to be delivered, and health professionals (psychologists, neuropsychologists) providing the intervention will get training with the manual before the REMINDER implementation. Postdoctoral level clinical psychologists (research team members) will lead both experimental harm (face-to-face vs. videoconference) interventions, and the professional delivering the program will be counterbalanced across delivery methods to avoid the experimenter biases.

Regarding the sessions’ structure, each session begins with a mindful exercise and ends with a discussion of the homework assignments. All sessions have a task of psychoeducation about a specific topic, a moment of sharing and reflection, and a practical exercise.

Table 1 Contents of the REMINDER program sessions

1	Introduction	In this session, participants will receive information about the program, establish the rules for the sessions and group functioning, and become aware of the practice of mindfulness.
2	REMIND the brain	This module aims to teach participants about brain health, identify modifiable risk factors for cognitive decline, and share protective brain activities. Participants will be challenged to recognize the importance of bringing the real self-closer to the ideal self and learn to value positive behaviours.
3	REMIND the goals	This module recognizes the importance of personal goals in stimulating change and commitment. Participants will learn to create SMART goals and identify barriers and facilitators to achieving them.
4	REMIND the attention	This module recognizes the importance of focus for cognitive and emotional well-being and goal achievement. Participants will learn about the importance of the present mind and the use of all the senses to promote mindfulness. This module also stimulates the auto-instructions of attention STOP-FOCUS to help solve the automatic pilot problem.
5	REMIND the memory	This module aims to: 1) Know how memory works, its limits, and its potential. Participants will be invited to share memory problems and memory protector habits. 2) This module also recognizes the importance of autobiographic memory on neuropsychological functioning. Participants will learn about the reminiscence concept and life revision as an essential practice for a good aging adaptation. 3) Additionally, they will identify key events in the lifeline as identity structuring. 4) This module also aims to learn to use mnemonic strategies in daily life. 5) Participants will practice internal mnemonic strategies. 6) This module will help to know and recognize the role of external memory aids in planning and recovering future events. Participants will be invited to training on the utilization of external memory aids.
6	REMIND the executive functions	This module aims to recognize the importance of executive functions in daily life and behavioural monitoring. Participants can discover the relationship between executive functions and goals by breaking down goals into tasks. They will also apply behavioural control techniques in daily life and train their cognitive flexibility in problem-solving.
7	REMIND the communication	This module aims to identify the importance of communication for a healthy brain and recognize facilitator communication strategies. Participants will train to have effective communication.
8	REMIND the socialization	In this module, the objective is to acknowledge the role of communication in cooperation between people. Additionally, participants will discover the importance of socialization in well-being and personal development.
9	REMIND the emotions, and I	This module aims to recognize the role of emotions in brain health. Participants will be asked to identify difficulties in emotional regulation and the risk factors associated with aging. They will train to develop a positive and realistic self-concept to improve emotional regulation.
10	REMIND the emotions and the others	This module aims to recognize the importance of self-compassion and self-concept in a crisis moment. Participants will be challenged to identify models of personal resilience. This module also enables recognition of the importance of a supportive network for individual autonomy and quality of life.
11	REMIND the learning	This last module aims to identify the key elements of cognitive, psychological, and social skills that should be improved daily to protect the brain. Then, it seeks to recognize a group's importance in realizing lifestyle changes. Participants will be invited to provide a global program evaluation during a shared snack.

REMINDER4carers harm

In this experimental harm only offered to MCI group of participants, they will be offered psychoeducation and support sessions to caregivers of MCI participants in parallel with the delivery of the REMINDER program to the patients. Research also demonstrates that increasing awareness of the support system regarding the disease and lifestyle change needs of the patients, promotes adherence and engagement of the latter in protective health behaviors (e.g., [35]). Therefore, ten sessions will be implemented, including both emotional support and guidance (including delivery of leaflets and contacts for further support) regarding relevant themes in caregiving, such as roles’ changing; uncertainty of care needs; planning the future and long-term care; caregiving well-being and self-care needs; communication skills; and grief and loss.

Waiting list control groups

After the 6-month follow-up period, participants in the control groups will be offered the REMINDER intervention (a more convenient delivery method), and they should not be taking any active interventions during the 6-months experimental harms’ duration.

Outcomes

The professional qualified to conduct pre-and post-intervention neuropsychological assessment will be blind to the intervention harm each participant was assigned. Participants will be assessed at baseline, post-intervention, and at 3, 6, and 18-month follow-up.

The REMINDER protocol will include a comprehensive protocol of both cognitive, emotional, and functional status (described below). The protocol lasts approximately 1-hour session.

Sociodemographic, clinical information

We will collect participants’ sociodemographic (e.g., age, marital status, education level, professional status) and clinical (presence of medical diagnosis, actual medication, sensory issues, mobility deficits, use of substances, and previous issues and hospitalization) information through a questionnaire developed by the researchers. Biological markers of neurodegeneration will also be collected at the baseline and post-intervention.

Primary Outcome

Given the multidomain nature of this intervention, we will consider as primary outcomes the following:

a) A cognitive function composite (selected measures z scores, incorporating Mini Mental Status Exam (MMSE) [36]; Orientation to time and place (from MMSE); Word List Total Recall Score (WMS-III) [37]; Category Fluency total [38]; Trails Part B [38].

b) Healthy lifestyle behaviours, measured with Healthy Lifestyle Assessment Toolkit (HLAT) [39]. This will measure adherence to physical activity, cognitive engagement, and diet and will be complemented with qualitative interviews for a subsample of participants.

These outcomes will be measured in all assessment time points (pre-, post-, 3-, 6-, and 18- months follow-up).

Secondary Outcomes

The secondary outcome, assessed at baseline, post-intervention, and at 3-months follow-up, will include:

Specific cognitive functions:

Global Cognition (Addenbrooke’s Cognitive Examination – Revised [40]; Episodic Memory (Word Lists) [37]; Verbal Initiative (Letters P, M, R and Categories Animals Fluency) [38]; Executive Function (Behavior Rating Inventory of Executive Functions- Adults (BRIEF-A) [41]; Working Memory (Weschler Adult Intelligence Scale (WAIS) – Digit Span Task) [42].

Perceived and performance-based functional status:

Adults and Older Adults Functional Assessment Inventory (IAFAI) [43]; University of California San Diego Performance-Based Skills Assessment (UPSA Brief) [44].

Psychosocial/ Mental Health indicators:

Geriatric Depression Scale (GDS-30) [45]; World Health Organization Quality of Life (WHOQOL-OLD 7) [46]; Lubben’s Brief Social Network Scale [47]; Psychological change (Clinical Outcome Routine Evaluation) [48]; Motivation (Motivation to Change Lifestyle and Health Behaviour for Dementia Risk Reduction (MCLHB-DRR) [49].

Biological markers of neurodegeneration:

Currently, the most robust blood-based biomarker is the neuronal cytoplasmic protein Neurofilament light chain (NfL). NfL is a sensitive but unspecific marker of axonal injury, with potential ability to rule-in or rule-out neurodegeneration and to assess its progression rate [50]. Therefore, the value of baseline and/or longitudinal measurements of blood NfL in predicting the course of cognitive decline has been verified in different neurodegenerative dementias, and in cognitively normal individuals [51]. Importantly, since blood NfL can detect axonal damage that has occurred in the last 3 months, it has also been used as an indicator of the treatment efficacy of disease-modifying treatments [52]. Other recognized important markers are neuroinflammation and cerebrovascular function alterations and/or blood-brain barrier (BBB) damage. Glial fibrillary acidic protein (GFAP), an intermediate filament protein mainly expressed in astrocytes of the central nervous system and soluble platelet-derived growth factor receptor-β (sPDGFRβ) a marker of BBB-associated capillary mural cell pericyte, respectively, are good candidates [53]. Such markers have also recently shown potential as early surrogates of cognitive dysfunction [54-56]. We will assess the levels of blood NfL, GFAP and sPDGFRβ in a subset of the study population (33% in all study harms) before and after the intervention period. Blood samples will be collected into serum separation tubes, centrifuged at 1500 g, 4^oC for 10 min. Serum will be separated, aliquoted and frozen at –80^oC in the same day of collection. Serum NfL and GFAP will be quantified simultaneously using the SiMoA (Single Molecule Array) Neuro-2Plex B multiplex kit in an SR-X platform (Quanterix, USA). Serum sPDGFRβ levels will be determined separately using an already described ELISA kit.

Participants

This study has a randomized, waitlist control design. We will recruit participants with increased modifiable risk factors for dementia. We will also recruit caregivers/relatives of MCI patients to participate with a randomized subset of the patients in one experimental harm of the Clinic. Those who meet the eligibility criteria will be invited to participate in the study and the baseline assessment. After finishing the baseline assessment, we randomly assign the participants to one of the study groups, to know – Community Trial: REMINDER or the Waiting List Control Group (Figure 1, for the trial flowchart); Clinical Trial: REMINDER intervention alone, REMINDER intervention + caregivers, or the Waiting List Control Group (Figure 2, for the trial flowchart). A researcher blind to the assessment procedure will conduct randomization, and then all participants will be informed about their assigned condition. Waitlist participants will be offered the REMINDER intervention after 6 months, and participants will ultimately be followed out to 18 months post-intervention (24 months total).

Figure 1. Flowchart of participants in the Community Trial

Figure 2. Flowchart of participants in the MCI trial

Sample Size

The sample size estimation was performed in “G*Power”, a statistical software program. Power analysis was performed and was based on both existing data on the effects of dementia risk reduction programs in a cognitive composite [24, 57] as well as in our preliminary feasibility study results that held small to medium effects (f>.20). Accordingly, for the Community trial, a total sample size of 244 was determined based on an expected power of .80 to detect small to medium effects (f>.20) in comparison analyses in the primary outcomes (e.g., cognitive composite; lifestyle change) (G*Power). Considering an expected dropout rate of 10%, a total sample size of 268 participants leads to an approximate required final expected sample size of 270 (135 per harm). For the Clinical Trial, the same power analysis was performed, and considering now three harms, a final sample size of 270 is distributed across harms, with 90 participants per harm.

Given the multifactorial higher risk of women developing dementia, we will take this into account in the sex/gender ratio of the sample recruited as well as in the efficacy analyses.

Recruitment

For the Community trial, we will approach the participants through traditional and social network advertisement (Project’s website - www.remindereomeucerebro; community and clinical recruitment settings with protocols with the University of Coimbra (Coimbra University Hospitals, Memory Clinics, Elderly Day Care Centres, and Senior Universities in Coimbra region). Then, we will screen the study participants and invite those meeting inclusion criteria to participate, sign a written consent form that details all the investigation procedures, and randomly assign the participants to the study harms. For the Clinical trial, general hospitals from three Portuguese regions (Coimbra, Trás-os-Montes, Porto) will be approached (after getting the ethics committee approval for each Local Health Unit board). Doctors will be approached to signalized MCI patients, who will be invited to participate in the study, sign the written consent form, and take the baseline assessment prior to be randomly assigned to the study harms.

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.

Assignment of interventions

Before the recruitment of participants into the intervention, a predetermined amount of study ID numbers will be randomly preassigned to each recruitment site (according to a pre-established recruitment ratio anticipated for each site). A researcher blind to the assessment procedure will conduct randomization using a computerized random number generator. 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 will be assigned a study ID number.

Implementation

Participants who consent and meet inclusion criteria will be randomized. Recruitment members will request randomization and receive a form with a randomization number, which they forward to another team member. Then, the patient will be informed of their treatment group, while recruitment staff remain blinded to group allocation.

Blinding (masking)

A blinded trained neuropsychologist will perform the neuropsychological assessment at the predicted time points, and another trained clinical neuropsychologist will deliver the REMINDER program under the supervision of the PI and remaining research team, distributed across recruitment sites. This researcher and the study coordinator will be responsible for database creation and completion, and the remaining research team will perform the data analysis.

Statistical methods

Statistically, we will analyse the program efficacy following intention-to-treat (ITT) and per-protocol (PP) principles following CONSORT recommendations [58], allowing to examine data from all randomized participants for the two trials (even those with missing values on outcome measures). Linear mixed models will be conducted to determine the effects of the intervention over time (time × group interaction effects) on primary and secondary outcomes. We will include sex/gender as a covariate in the efficacy analysis. Additional statistical analyses such as two-wave latent change score models, reliable change index, Chi-square tests, and within-group effect sizes will be performed, as well as a mediator and moderator analysis. The generalized estimating equation (GEE) method will be used to analyse the estimated regression coefficients (i.e., the effect estimates) for these outcomes (functionality, global cognition, dementia risk score) concerning neurobiological data (neural plasticity and NfL). The GEE method extends standard regression analysis, accounts for the correlation between repeated measurements, and is more robust to violations of normality. Initial data analysis will be done using IBM SPSS Software, version 28.0 (IBM Corp, Armonk, NY, USA), and more advanced modeling will be performed using R Program (R Core Team, 2022).

Ethics and dissemination

Research ethics approval

The Ethics Committee of the Faculty of Psychology and Educational Sciences of the University of Coimbra (CEDI/FPCEUC:62/8) approved this study, registered in Clinical Trials (ClinicalTrial.gov Identifier: NCT05296980). The project will be also submitted for approval to the collaborative hospitals Ethics Committees (CHUC – Centro Hospitalar e Universitário de Coimbra, CHTMAD – Centro Hospital Trás os Montes e Alto Douro; ARS-C - Associação Regional de Saúde do Centro; ACES – Grande Porto II – Agrupamento de Centros de Saúde do Porto II) in which the clinical and at-risk sample recruitment will take part.

Consent or assent

All participants must sign the approved informed consent forms before any study-related processes.

Confidentiality

All participants will be informed about the study-related issues and the confidentiality of the researcher’s duties. However, they must be fully aware of the voluntary nature of their participation and the right to refuse to participate or withdraw at any time and without penalty.

Access to data

This project will implement data anonymization procedures to protect personal data. Only a limited and well-identified group of people will have access to parts of the data, complying with the General Data Protection Regulation (GDPR) laws.

Declaration of interest

No potential conflict of interest was reported by the author(s).

Author Contribution

Ana Rita Silva (ARS), Catarina Baptista (CB) and Margarida Lima (MPL) formulated the research question and designed the study. The methods and program design was developed by ARS, CB, MPL, Rosa Afonso (RMA) and Salomé Pinho (SP), the markers of neurodegeneration methods developed by Inês Baldeiras (IB) and the full paper was drafted by ARS and CB with substantive comments and revisions provided by all authors.

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REMINDER program: a randomized controlled trial protocol of a neuropsychological intervention for lifestyle modification in older adults at risk of dementia

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