Introduction: The Insulin resistance itself has been recognized as an independent risk factor for dementia development. Insulin plays an important role in the regulation of muscle function and the processes of learning and memory. Insulin resistance is associated with increased inflammation and oxidative stress. These processes are involved in the pathophysiology of neurodegenerative diseases. Thus, reducing IR could have implications for improving metabolism, muscle, and cognitive function.

Methods and analysis. The investigators will conduct a randomized, double-blind, placebo-controlled clinical trial in which a multidomain program, including an aerobic and cognitive exercise program, will be evaluated. The latter is an exercise program conducted on a checkered mat and will be randomized to participants receiving turmeric plus black pepper or placebo. Participants are affiliated with the Mexican Social Security Institute (IMSS) and are between 55 and 74 years old. The program will last for 24 weeks; after 52 weeks, it will be repeated. The outcomes that the investigators will evaluate are: global cognitive function, specific cognitive function, and the investigators will evaluate serum markers of inflammation, oxidative stress, and GSK-3beta levels. The effect of the interventions on each variable will be analyzed by ANOVA, and a multivariate analysis study with multiple linear regression will be conducted.

Ethics and dissemination of the study: the study was approved by the IMSS National Ethics and Research Committee all participants provided written informed consent prior to their participation.

Dementia is characterized by cognitive impairment, which affects independence in activities of daily living (1). Worldwide, approximately 47 million people were living with dementia in 2015, and before the COVID-19 pandemic, the number of cases was expected to triple by 2050 (2). The prevalence of dementia in Latin America and the Caribbean is 10.66%, and dementia is more prevalent in women than men (7.26%).

Observational studies have shown that dementia and cognitive decline can be prevented by reducing vascular risks and improving healthier lifestyles (6). The key is to modify lifestyle habits before the development of disease symptoms. To achieve this, it is important to characterize populations with intact cognitive function or with some concern without symptoms of cognitive decline (6).

Interventions to treat dementia have been nonpharmacological, including nutrition, cognitive stimulation, physical exercise, and multi-domain (combination of more than two components or domains). However, the best results for dementia prevention have been for multi-domain interventions in individuals with intact cognitive function or those with some concerns (10). The domains included in all multi-domain interventions were physical activity, nutrition, and cognitive training. The Mind and Movement for Cognitive Health Program (MeMo Health-Cog) is a program that includes three basic components: a) a moderate physical activity routine through a one-hour/day routine of combined aerobic exercises, b) cognitive training with the checkered mat and c) a motivational educational program that consists of weekly talks on topics of healthy active aging, sports for older adults, basic nutrition recommendations, health topics, and socialization; these talks last between 10 and 15 minutes. Physical and cognitive activities are a one-hour routine each day, and they can be performed three days a week. The duration of the entire program is 24 weeks. It is important to mention that the educational program encourages light physical activities with the 24-hour healthy educational program, which are recommendations of Canadian origin that allow improving behaviors related to movement, that is, moderate and light physical activities, adequate sleep duration, and limitations of sitting (13).

An important and emerging concept is insulin resistance at the brain level, where insulin signaling plays crucial roles in physiology and therefore affects cognitive function. Altered insulin signaling in brain tissue contributes to Alzheimer's disease (AD) through increased beta-amyloid and tau neurofibrillary tangle formation and other brain damage mechanisms. Insulin resistance not only affects systemic metabolism and directly influences the brain by altering insulin-related brain pathways (20).

b. Mechanisms of insulin resistance, inflammation, and oxidative stress The molecular mechanisms of type 2 diabetes (T2DM) are characterized by an alteration in the regulation of carbohydrate, lipid, and protein metabolism, as a consequence of a decrease in insulin secretion and resistance to its effect (21).

Insulin Resistance (IR). Insulin is a major regulator of carbohydrate, lipid, and protein metabolism. It acts through a signaling cascade involving the receptor, substrate, and various signaling molecules (22, 23). Insulin resistance is defined as an inappropriate response to insulin-mediated glucose control. The skeletal muscle is a quantitatively central tissue for insulin-stimulated glucose disposal, and liver and adipose tissue are qualitatively critical sites for glucose-induced insulin signaling. These tissues are central to understanding the mechanisms responsible for insulin resistance.

Inflammation and oxidative stress are associated with the alteration of insulin signaling, which increases IR. In turn, IR increases oxidative stress and therefore inflammation. Forming a systemic loop of insulin resistance, inflammation and oxidative stress is present in obesity, diabetes, vascular dementia, and Alzheimer's disease (AD); since it affects the function of various organs such as the liver (increases gluconeogenesis), muscle (decreases glucose consumption and loss of muscle mass), adipose tissue (increases adipose tissue), brain (increases neurodegeneration and reduces brain resilience) and cardiovascular system (endothelial dysfunction and vascular damage) (26).

Oxidative stress and insulin resistance (IR). Inflammation promotes oxidative stress and insulin resistance and can also increase GSK-3β expression and alter mitochondrial function, which in turn generate reactive oxygen species (ROS) and nitrogen species (RNS), which react with lipids, proteins and nucleic acids, causing their oxidation and generating neurotoxic consequences (33). Lipid peroxidation, one of the main forms of damage associated with oxidative stress, affects brain tissue and is an important marker of neuronal damage. This damage can be measured by the formation of malondialdehyde (MDA) and 4-hydroxynonenal (HNE), and has been established as a clear factor associated with Alzheimer's disease (AD) (35). In addition, other markers of oxidative stress, such as glutathione levels, are correlated with mild cognitive impairment and AD (36). Other methods to assess oxidative stress include the measurement of protein oxidation, which analyzes the formation of quinones. The accumulation of beta-amyloid (Aβ) plaques and phosphorylated Tau protein in people with type 2 diabetes (T2DM) is associated with inflammation, oxidative stress and insulin resistance (37). At the brain level, insulin reduces the activity of the action of GSK3-β (glycogen synthase kinase-3 beta) as part of its intracellular signaling. This enzyme phosphorylates Tau protein and promotes the division of amyloid precursor protein (APP), and increases the expression of the enzyme BACE-1, resulting in an increase in the amount of beta-amyloid and greater expression of NF-κB

Another function of insulin in the brain is to facilitate brain plasticity, which favors memory and learning by promoting the formation of dendritic spines and synapses; insulin contributes to repair and neuro-protection processes (43)

Since ancient times, functional foods and exercise have been combined to reduce aging-related diseases (49). Dietary choices should have neuroprotective effects. Supplements can cause alterations in signaling pathways, such as AKT, which are important for preventing neurodegeneration because AKT inhibits the activity of GSK-3β, the main enzyme that phosphorylates Tau. Several plants and fruits have shown promise in reducing the progression or risk of dementia, and among the research, curcumin stands out (50). Turmeric is a herbaceous plant whose root, known as rhizome, has been traditionally used both as a spice and for medicinal purposes. Curcuminoids isolated from this plant have anti-inflammatory and immunomodulatory properties.

The main effects attributed to turmeric on health include:

1. Antioxidant effect: it increases the activity of enzymes such as catalase, superoxide dismutase (SOD), glutathione peroxidase and heme-oxygenase (53).
2. Chronic anti-inflammatory effects have been demonstrated in animal studies where it has been shown that inflammation is reduced by decreasing TNF-α levels and suppressing NF-κB activation, as well as by decreasing the expression of inflammatory enzymes such as iNOS, COX-2, lipoxygenase and xanthine oxidase (55). This process reduces the expression of inflammatory cytokines such as IL-1β, IL-6, IL-5, IL-4 and IL-2.
3. Likewise, neuroprotective effects have been observed in animal studies, where turmeric has been shown to inhibit the formation of β-amyloid oligomers and β-amyloid aggregation, in addition to reducing tau hyperphosphorylation. A reduction in neuroinflammation and acetylcholinesterase (AChE) activity was also observed, which could improve memory (56, 57, 58, 59).
4. Regulation of GSK-3β: Studies in mice and clinical trials in humans have shown that curcumin can reduce GSK-3β activity, which may have beneficial effects on insulin resistance and lowering insulin levels (60,53), with this being the only randomized clinical trial that applied 500 mg/day of turmeric for 24 weeks, but improvement in cognitive function has not yet been considered.

Study hypothesis:

The multidomain intervention (MeMo-Health-Cog) with turmeric dietary supplement is more effective than the multidomain intervention (MeMo-Health-Cog) with placebo in improving insulin resistance by 5%, global cognitive function by 3%, neuropsychological functions, physical performance by 5%, and neuroprotection biomarkers by 5%. Moreover, these effects are expected to be maintained for up to 28 weeks after the intervention is implemented.

Sample size:

The investigators used a sample size calculation for a superiority clinical trial, using the formula of Zong (2009) and Wang (2020), considering alpha less than 0.05, a power of 80%, the investigators considered a superiority of 5% for the intervention group, which was considered clinically significant. the investigators considered differences reported in previous clinically acceptable studies, as well as taking into account the standard deviation. For general cognitive function (MOCA) = 0.20 (0.05), for subjective cognitive function 6 (0.05), Trail Making test part A 0.20 (0.05), Trail Making test part A 0.20 (0.05), verbal learning test (RAVLT-immediate) 0.44 (0.05), verbal test (RAVLT-delayed) 0.58 (0.05), verbal fluency = 0.46 (0.05); GSK-3 beta = 0.40 (0.05), HOMA IR 0.1 (0.05); 4 4 hydroxynonenal 0.12 (0.05), MDA (malondialdehyde) 0.18 (0.05), TNF alpha 2.8 (0.05), TNF alpha effect on RALVT 3.3 (0.05), IL-6 (0.05), IL-1 0.001 (0.3). Taking these parameters into account, the total sample size is 64 participants, but if the investigators add that we need to do a multivariate analysis with at least 3 variables (inflammation, insulin resistance, and oxidative stress) to explain the improvement in patients, the investigators consider that require 50 patients per group, that is, 100 patients in total.

Intervention implementation. The study will be coordinated by the principal investigator of the Epidemiology and Health Services Research Unit of the IMSS in Mexico City, National Medical Center Siglo XXI. The interviews will be conducted in a place assigned by the UMF 4; and the training site. The Education and Research Coordinator at the UMF headquarters will be available to resolve emergencies or any event requiring clinical attention. The experimental group consisted of 60-min sessions conducted three days a week for 24 weeks. Each session will be guided by a health professional with experience in nursing who was previously trained to train with the MeMo-Salud-Cog-4 program. The trainer will apply aerobic exercises and then show different step patterns and ask the participants to observe, memorize and repeat these patterns on the checkered mat. The maximum number of participants per group will be 12.

Motivational strategies. A follow-up system will be an important strategy to prevent dropouts and low adherence to the program. This system will be complemented with motivational phone calls to participants who missed group sessions or who do not take the supplement, as well as to people who missed it due to medical appointments or personal commitments. At the end of the program, the program is extended to complete the sessions at 80%. In addition, the study includes a motivational educational program that consists of group sessions of 10 to 15 minutes to explore topics related to active aging, sports for the elderly, health issues, nutrition and socialization through the exchange of experiences about past events. This program is given before or after the session, depending on the group's decision. The talks have educational material in which the topics are briefly explained on a WEB page and in a book where more information is provided. The instructor, who is a trained health professional, gave the talk through the WEB page and the participant received a book for more information on the topic.

Evaluation. The research will include 3 evaluations: at baseline, 24 weeks, and at 52 weeks. The outcome variables of the study will be measured at each evaluation, as will the covariates. The investigators will measure the participants' adherence to the program, defined as 80%. Finally, the reasons for abandoning the program and poor adherence will be documented. The evaluation will be performed by health professionals with internal medicine and gerontology specialties.

The study included the following covariates: age, biological sex, formal education level, current employment and status (active, retired, volunteer, self-employed), marital status (married, divorced, single, in a common-law relationship, other), current living status (living alone, with wife or husband, living with or without children), comorbidities (hypertension, orthopedic, cardiac, vascular, hepatic or renal disorders), baseline physical activity prior to the study, ideally defined as more than 150 minutes per week of moderate physical activity or more than 75 minutes per week of intense vigorous activity, or an equivalent combination); moderate/intense (less than 149 minutes per week of mild or moderate activity less than 74 minutes of vigorous or intense activity, or its equivalent); and poor (no physical activity, neither moderate nor intense), the presence of the APOE ε4 allele was measured.

Statistical analysis. The researcher will first perform a descriptive analysis of older adults, their results in each assessment, and the distribution of quantitative variables using Kolmogorov-Smirnov as a test to assess normality. Normally distributed variables will be analyzed using means and standard deviations, measurements with free distribution will be presented using median and 25th and 75th percentiles, and categorical variables will be described using frequency and percentage. Second, for each evaluation, the researcher will be able to compare the variables of the groups before and after, the magnitude of the change in these, and their comparisons between groups. For comparisons between groups, the investigators will use the Student t-test (for those with a normal distribution) and the Mann-Whitney U test (for those with a non-normal distribution). The effect of the intervention on the outcome variables will be estimated by measuring the difference in change from baseline to measurements at 24 and 52 weeks, and a comparative analysis of the magnitude of the differences between groups will be performed

The analysis of the difference in means by intervention and control group for continuous and normally distributed response variables will be reported as the mean and standard deviation for variables with normal distribution, and the comparison of the means between t0-t24 weeks and t24 weeks - t52 weeks will be done using the paired t-Student test. For variables without normal distribution, the comparison of medians at t0-t24 weeks and t24 weeks-t52 weeks will be obtained from paired samples using the Wilcoxon test. In both cases, a significant difference will be considered with a value of p less than 0.05. For discrete variables, the difference in proportions will be obtained using the chi-square test, using time zero as reference. The comparison of the effect of the intervention and the control from t0 to t24 weeks for the continuous outcome variables will be estimated by estimating the effects and 95% confidence intervals of the differences in the means ("d") over time using the univariate general linear model, regression analysis, and two-factor analysis of variance (ANOVA). This analysis will include covariates and interactions, contrasting both balanced and unbalanced models, and generating effect estimates with 95% confidence intervals. To check assumptions, a robust analysis of variance will be performed for deviations from normality, ensuring that the assumption of symmetry and homogeneity of variances is met (p more than 0.05). In a second model, a comparison analysis of the effect of the intervention and the control from t24 weeks - t52 weeks will be performed. For variables that do not comply with normality, Generalized Estimating Equations (GEE) will be used, a method suitable for repeated measurements that allows the inclusion of covariates and interactions. The interpretation of the results in favor will be considered when the p value less than 0.05.

For discrete variables, the effect estimation will be performed using logistic regression analysis to estimate the Relative Risk and 95% confidence intervals, reporting raw values and those adjusted for covariates selected based on their clinical or statistical relevance. Models will be obtained for the comparison of the intervention and control t0-t24 weeks and t24-t52 weeks. The interpretation of the results in favor will be considered when the p value less than 0.05.

In both analyses, the interaction of participants with low adherence will be included considering the 25% percentile.

The handling of lost values through multiple imputation or models that handle incomplete data will be considered, ensuring the integrity and validity of longitudinal statistical analyses. The analyses will be performed using Stata V.14.0 software (Stata Corp) and IBM SPSS version 23.

Conditions:

Cognitive Decline Insulin resistance.

Keywords:

cognitive decline multidomain intervention turmeric plus papering.

Study Design

Study Type: Interventional Primary Purpose: Prevention Study Phase: N/A Interventional Study Model: Parallel Assignment A double-blind randomized clinical trial entitled "Mind and Movement: Towards the Cognitive Health of Older Adults 4" will be conducted. The study will include a intervention group and one control group: (1) a multidomain intervention with double-task exercise program with a squared mat led by a coach (a health professional) for 24 weeks plus a turmeric capsule plus black pepper every 12 hours; and a control group included a multidomain intervention with double-task exercise program with a squared mat led by a coach (a health professional) for 24 weeks plus a placebo capsule every 12 hours.

Number of Arms: 2

Masking: Double (Participant, Investigator) To ensure that the groups are balanced regarding varying levels of education, study participants were not stratified and randomly allocated in blocks of four to one of the intervention groups or the control group. An independent researcher who will not participate in the study will use the Random Allocation Software to generate the allocation sequence. Each stratum will have its own seed. This researcher will generate uniform random integers to create the allocation order within each block. She will hold the randomization file on her computer and will give out the allocations of individual participants one at a time to the three groups. The allocations will be concealed from participants and the study staff involved in enrollment and baseline evaluation.

The recruitment and application of the intervention for groups in Care Unit 4 for IMSS.

Allocation: Randomized

Enrollment: 100

Arms and Interventions

Arms

Active Comparator: control group included a multidomain intervention with double-task exercise program with a squared mat led by a coach (a health professional) for 24 weeks plus a placebo capsule every 12 hours.

Assigned Interventions

Mind and Movement for Cognitive Health in the OlderAdult 4" The intervention group will consist of 60-minute training sessions delivered three days a week during a 24-week period. Each session will be guided by a health professional certified to coach SSE. The make-up of each session is: 1) 5 minutes of warm-up; 2) 30 minutes of moderate-to-strong intensity aerobic exercise, 3) 5 minutes of aerobic cool-down, 4) 20 minutes of double -task exercise (mat); and 5) 5 minutes of cool-down stretching (this times does not count as activity) plus a capsule with 500mg of turmeric and 5mg of black Pepper.

Other Names:

Aerobic and stength exercise programa. Double-task exercise by a health professional older adults and their caregivers will participate in the same SSE program led by coach for 24 weeks.

Outcome Measures

Primary Outcome Measure:

1. General Cognitive funtion General cognitive function assessed by the Montreal Cognitive Assessment (MoCA) test on a scale of 0-30 points.

Scores are interpreted as follows: >26 indicates no dementia, 18-26 mild cognitive impairment, 6-10 moderate dementia, and <6 severe dementia. [Time Frame: 0, 24 and 52 weeks]

[Time Frame: 52 weeks] Specific domains of cognitive function Measured through composite scores: Executive function/mental flexibility will be measured with the Trail Making Tests, Part A and Part B. The results for both TMT-A and TMT-B are reported as the number of seconds required to complete a task. Processing speed (using the Digit Symbol Substitution Test) will be measured as the total correct number-symbol matches achieved in 90 seconds. Verbal learning and memory will be assessed through Rey's Auditory Verbal Learning Test (RAVLT) that consists of documenting the number of words remembered from a list of 15 words presented in two separate moments; this test allows evaluation of the RAVLT-Immediate and RAVLT-Percent Forgetting. Verbal fluency (semantic, animal naming, and phonemic) will be measured by using the Controlled Oral Word Association Test and assessed through the total number of words identified by category and letter.

[Time Frame: 0, 24 and 52 weeks]

Metabolic biomarkers, inflammation and oxidative stress damage biomarkers: HOMA-IR, glycosylated hemoglobin, markers of oxidative stress (malondialdehyde, 4-hydroxi-2-nonenal, Thiol groups, carbonyl groups, glutathion peroxidase activity), GSK-3beta, IL-1, IL-6, TNF-alpha.

[Time Frame: 0,12, 24 and 52 weeks]

Cognitive reserve episode. Capacity that enables an individual to cope with and/or recover from the impact of a neural injury or a psychotic [Time Frame: 0 and 52 weeks]

Secondary Outcome Measure:

Usual walking and dual-task gait Usual walking and dual-task gait will be evaluated through motion capture during the six-minute walk test (6MWT), which requires participants to walk back and forth across a 30-metre area at a comfortable pace for six minutes. The fixed distance utilized by 6MWT allows determination of gait speed (i.e., v=d/t); however, this test will also be coupled with infrared stride analysis, which will allow for a more precise evaluation of gait speed, stride length, and stride variability under usual and dual-task conditions. These procedures will provide a number of valid and reliable gait outcomes through the synchronization of mobility data via eight infrared cameras, six force plates, and electromyography.

[Time Frame: 52 weeks]

Quality of life as measured by SF-12 Older adults' health-related quality of life (QoL) will be measured by the short form (SF-12) of the Medical Outcomes Survey questionnaire, comprised of 12 items. Physical and mental scores will be calculated using an algorithm to convert each item response into standardized values according to specific predetermined weights. Summary scores for each component range from 0-100 and are interpreted as low QoL (close to 0) and high QoL (approaching 100).

Cardiovascular biomarkers and endothelial function: MCP-1, ICAM VCAM and Selectin This is the ability of circulating vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intercellular adhesion molecule-1 (ICAM-1) to serve as molecular markers of atherosclerosis and predictors of incident cardiovascular disease.

[Time Frame: 52 weeks]

Inclusion Criteria:

• Minimum Age: 55 Years Maximum Age: 70 Years Sex: All Gender Based: No Accepts Healthy Volunteers: No Criteria: Inclusion criteria.
• 1. With 55-70 years of age.
• 2. They have self-reported cognitive concerns (ie, have answered "yes" to the question: "Do you feel like your memory or thinking skills have gotten worse recently?").
• 3. The participant has insulin resistance measured with HOMA IR index > 2.5.
• 4. They demonstrate functional independence in activities of daily living and instrumental activities of daily living.
• 5. They have symptoms or signs of underlying cognitive dysfunction without a diagnosis of dementia (ie, confirmed by a review of their health records and a Mini Mental State Exam [MMSE] score> 24).
• 6. If the participant are a woman, one year after having gone through menopause.

Exclusion Criteria:

• 1. With depression (score> 15 according to the Center for Epidemiological Studies Depression Scale - Revised [CESD-R]).
• 2. With clinically significant neurological or psychiatric disorders (eg, Parkinson's, schizophrenia).
• 3. With a recent severe cardiovascular event (eg, myocardial infarction, stroke).
• 4. With a major orthopedic condition (eg, severe osteoarthritis).
• 5. With blood pressure that is unsafe for exercise (ie,> 180/100 mmHg or <100/60 mmHg).
• 6. With a severe visual or auditory impairment.
• 7. With an unwillingness to adhere to the intervention schedules.
• 8. Patients with active cancer, who are undergoing chemotherapy, radiotherapy, or other treatments aimed at eradicating cancer and who have been undergoing treatment during the last year.
• 9. Elimination: participants with incomplete data and who have not complied with the intervention by 80%.

Data will be shared on written request

The researchers will use key-labeled bottles to designate placebo vs turmeric; the participants, doctors, and staff do not know which group each bottle corresponds to. Only two people from the research team know which group each bottle corresponds to.