The goal of this 26-week trial is to learn if creatine supplementation and resistance training (i.e., weightlifting; exercise that increases muscle mass), alone and together, impact cognition, brain health, and physical function in older adults with mild cognitive impairment. Previous studies have shown that resistance training improves cognition and brain health in older adults. Creatine is naturally occurring in the human body and is known to decline with age. Studies have shown that creatine increases muscle mass and bone density in older adults when supplemented. Some research has suggested that creatine may also improve cognition and brain health. However, little is known about how creatine supplementation affects the aging brain and body alone and when combined with resistance training, especially in those with known cognitive impairment.

In this study, participants will be randomly assigned to one of four groups: 1) creatine and resistance training, 2) placebo and resistance training, 3) creatine and active control (balance and tone classes), or 4) placebo and active control. Participants in the creatine groups will take creatine every day during the study. Participants in the placebo groups will take a look-alike substance that contains no drug every day during the study. Participants in the resistance training groups will attend three 60-minute classes per week that target each major muscle group and will increase in difficulty during the study. Participants in the active control group will attend three 60-minute classes per week that will consist of balance, stretching, and range of motion exercises. This group accounts for variables such as physical training received by traveling to the training centres, social interaction, and changes in lifestyle secondary to study participation.

Researchers will collect information before and after the 26 weeks to see if creatine supplementation and/or resistance training have any effects on cognition, brain health, and/or physical function. The investigators suspect that both creatine supplementation and resistance training will improve cognition, brain health, and physical function alone. However, it is thought that the combination of creatine supplementation and resistance training will improve cognition, brain health, and physical function more.

Research objectives:

To evaluate the effects of 26 weeks of creatine supplementation on its own and in combination with progressive resistance training in community-dwelling older adults with mild cognitive impairment on:

1. visuospatial working memory (Primary Objective);
2. executive function (working memory, inhibitory control, and mental flexibility), functional mobility, muscle and grip strength, bone density, cerebral blood flow, and blood-based biomarkers for brain health and cognitive decline (Secondary Objectives); and
3. resting state functional activity, hippocampal volume and structural integrity, and key metabolite concentrations in the brain (Exploratory Objective).

Hypotheses:

It is hypothesized that 26 weeks of creatine supplementation and resistance training in community-dwelling older adults with mild cognitive impairment will: 1) increase visuospatial working memory performance; 2) improve executive function, functional mobility, strength performance, bone density, cerebral blood flow, and blood-based biomarkers for brain health and cognitive decline; and 3) increase resting state functional activity, volume and structural integrity in the hippocampus, and concentrations of key metabolites in the brain.

Methods:

Screening: Participants interested in the study will reach out to researchers via phone or e-mail. Interested participants will be sent the Letter of Information via e-mail to get more detailed information about the study. Before a baseline assessment is scheduled, investigators will complete an initial screening over the phone with all participants to ensure that study eligibility is met. The Physical Activity Readiness Questionnaire (PAR-Q) will be administered over the phone as part of initial screening to ensure that they can partake in exercise. At this time, participants will have an opportunity to ask questions. Those who are eligible and still interested in participating will be scheduled to come into the lab for baseline assessments.

Baseline assessments: When participants arrive in the lab, the researcher will go over the consent form with them, answer any additional questions they have about the study, and obtain informed written consent. At this time, participants may also consent to participate in the optional MRI portion of this study. Participants will then complete baseline assessments. Total time to complete baseline assessments in the lab (excluding MRI) will be ~2.5-3 hours. For those participating in the MRI component, this will be scheduled for another separate visit (1 hour).

Randomization: Once participants complete baseline assessment, they will be randomly assigned to one of the four conditions. Group allocation will be determined by an online randomizer (randomization.com). The sequence will be held remotely by the PI and will not be revealed until after baseline assessments.

Descriptors and covariates:

1. Anthropometry (height, weight)
2. Demographic information via general questionnaire (e.g., age, sex, gender, ethnicity, education, socioeconomic status)
3. Global cognitive function (Montreal Cognitive Assessment, MoCA; Mini-Mental Status Examination, MMSE). MoCA is used as a screening tool for mild cognitive impairment. This test assesses cognitive ability in the domains of attention and concentration, executive functions, memory, language, visuo-constructional skills, conceptual thinking, calculations, and orientation. Maximum score is 30. The MMSE is used as a screening tool for cognitive impairment. This 11-item test assesses global cognitive function in the domains of orientation, registration, attention and calculation, recall, and language. Maximum score is 30.
4. Physical activity levels (Physical Activities Scale for the Elderly, PASE). Used to measure the level of self-reported physical activity, and consists of 12 questions about leisure, household, and work-related daily activity.
5. Mood (Depression Scale, GDS).The GDS is a 15-item questionnaire used to test for the presence of depression. If depression is suspected, the PI will ensure that the participant is provided with a copy of the questionnaire and will advise the participant to make an appointment with their family physician to discuss the results.
6. Number of co-morbidities (Functional Comorbidity Index, FCI). The FCI is an 18-item list of diagnoses used to determine co-morbidities.
7. Health-related quality of life (Short Form Health Survey, SF-12). A self-reported questionnaire that measures a person's health-related quality of life and functional health status. Developed as a shorter alternative to the original SF-36 survey, the SF-23 assesses eight different health domains (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health) and provides summary scores for physical and mental health. Scores range from 0-100, with higher scores indicating greater health status and quality of life.
8. Loneliness (UCLA, Loneliness Scale). A 20-item self report measure on loneliness and interpersonal problems.

Adherence: All participants will be asked to record their supplement consumption on a calendar, which will be returned to the lab weekly. Exercise class attendance will be recorded each session by instructors. Participants will be encouraged to adhere to both the supplement protocol and exercise classes. The investigators will implement the following strategies to promote participant engagement:

• Semi-monthly newsletters that will feature personal accomplishments of participants (with permission) and study updates, for example.
• Investigators will follow up with participants who have missed supplement doses or exercise sessions to discuss barriers and strategies to overcome them on an individual basis.

If participants miss classes due to illness/travel, they will be scheduled to make up missing classes as soon as possible. If participants miss classes without notifying investigators in advance, investigators will call to remind them about their classes and encourage increased compliance.

During the 26-week intervention, participants will also complete the following assessments:

1. PASE (described in baseline assessments) - This will be used to monitor exercise outside of the program and will be administered at the last exercise session of each month.
2. Falls - Because declines in mobility are known to co-occur with declines in cognition, the investigators will monitor falls throughout the study duration to further characterize our sample. Participants will be asked to note falls in their calendar if they occur, which as mentioned above will be returned to the lab weekly for review by instructors.
3. Dietary intake - A three day weighed food record will be used to assess nutrient and energy intake at baseline and endpoint. Participants will record their dietary consumption over three days per month (two weekday and one weekend day). They will be instructed on how to do the food record at the first exercise session and will be asked to return it by the last exercise session of that month. The endpoint food record will be given to participants at the first session of the last month of the intervention and they will be asked to return it by the last exercise session of the month. A dietetic student will assist in analyzing this data.
4. Real-time physical activity levels will be monitored using wearable accelerometers (ActiGraph ambulatory monitoring wearables). Participants will be given the accelerometer to wear on their wrist for at baseline (one week during the first month of the intervention) and endpoint (one week during the last month of the intervention). This will allow objective quantification of energy expenditure, metabolic equivalent of task rates, steps, physical activity intensity, sedentary bouts, and sleep latency. They are Bluetooth enabled for real-time data uploads and include a wear-time sensor to assess compliance.

Final assessment: All baseline assessments will be completed at endpoint (26 weeks). The sub-set of participants at baseline who underwent MRI will also undergo the MRI protocol at endpoint.

Data analysis: Behavioural data (cognitive assessments, mobility, and physical measures) will be analyzed in SPSS. Primary and secondary outcome measures will be examined using a two-way ANCOVA to examine main effects of creatine supplementation and resistance training as well as the interaction between the two factors. The investigators will use the intention to treat principle where all randomized participants will be included in the final analysis regardless of adherence to the intervention. MRI data will be analyzed in Freesurfer and FSL. MRI/MRS data will be analyzed in collaboration with an expert who is familiar with processing this data. Investigators will examine changes over the intervention and compare these changes between groups.

Significance of research: This research is the first to address a critical gap in the literature by examining the effects of creatine and resistance training alone and in conjunction on various measures of physical function, cognitive function, and brain health in older adults with MCI. In the context of an aging population and given the overall safety and accessibility of creatine and resistance training, the findings from our study may inform biomarker-driven, non-pharmalogical strategies and interventions to offset or defer further cognitive decline in older adults with MCI.

To be eligible to participate in this study participants must:

1. be 60 years of age or older,
2. live independently in the community,
3. have normal or corrected-to-normal vision and hearing,
4. read, write, and speak English fluently,
5. be right-handed,
6. have subjective feelings of memory decline in the past 5 years,
7. have MoCA scores 19-25/30 (assessed at baseline session),
8. be able to exercise at a moderate pace using resistance training for 60 minutes 3x/week,
9. receive clearance from a physician to participate in an exercise program, and 10) receive confirmation from a physician that they meet all criteria to be included in this study.

Participants are ineligible if they:

1. cannot partake or commit to exercise training 3x/week for 26 weeks or have regularly (>1x/week) engaged in exercise training over the past 3 months;
2. cannot partake or commit to consuming a daily supplement for 26 weeks or consumed nutritional supplements containing creatine monohydrate over the past 3 months;
3. have a known allergy to creatine monohydrate or dextrose;
4. have been diagnosed with a neurological disorder (e.g., Alzheimer's disease, Parkinson's disease);
5. have pre-existing kidney disease, heart disease, or liver abnormalities;
6. have one or more uncontrolled chronic or psychiatric conditions (e.g., hypertension, diabetes, depression, anxiety);
7. are taking medication that may impact kidney function (e.g., non-steroidal anti-inflammatory drugs, such as ibuprofen and naproxen); or
8. are ineligible or uncomfortable with MRI (have metal or electronic implants, claustrophobia) or blood sampling.

Participants, physicians, and researchers who assess outcomes at endpoint will be blinded to group allocation.