Skip to main content
  • Study Protocol
  • Open access
  • Published:

Protocol for a single-arm, pilot trial of creatine monohydrate supplementation in patients with Alzheimer’s disease



Impaired brain bioenergetics is a pathological hallmark of Alzheimer’s disease (AD) and is a compelling target for AD treatment. Patients with AD exhibit dysfunction in the brain creatine (Cr) system, which is integral in maintaining bioenergetic flux. Recent studies in AD mouse models suggest Cr supplementation improves brain mitochondrial function and may be protective of AD peptide pathology and cognition.


The Creatine to Augment Bioenergetics in Alzheimer’s disease (CABA) study is designed to primarily assess the feasibility of supplementation with 20 g/day of creatine monohydrate (CrM) in patients with cognitive impairment due to AD. Secondary aims are designed to generate preliminary data investigating changes in brain Cr levels, cognition, peripheral and brain mitochondrial function, and muscle strength and size.


CABA is an 8-week, single-arm pilot study that will recruit 20 patients with cognitive impairment due to AD. Participants attend five in-person study visits: two visits at baseline to conduct screening and baseline assessments, a 4-week visit, and two 8-week visits. Outcomes assessment includes recruitment, retention, and compliance, cognitive testing, magnetic resonance spectroscopy of brain metabolites, platelet and lymphocyte mitochondrial function, and muscle strength and morphology at baseline and 8 weeks.


CABA is the first study to investigate CrM as a potential treatment in patients with AD. The pilot data generated by this study are pertinent to inform the design of future large-scale efficacy trials.

Trial registration, NCT05383833, registered on 20 May 2022.

Peer Review reports


Alzheimer’s disease (AD) affects more than 1 in 8 Americans over the age of 65 and is expected to grow in prevalence over the coming decades [1]. Historically, the pipeline of therapy development has been relatively futile, leaving few therapeutic options for patients with AD [2]. Much effort in advancing therapies in AD has been focused on halting deposition of and removing amyloid-beta (Aβ) plaque deposits in the brain, a pathological hallmark in the development of AD. Although recent trials suggest new treatments may be promising for removing Aβ from the brain [3, 4] and modestly improving cognitive symptoms in humans with AD [5], it is likely that additional therapies will also be required to treat and prevent symptomatic AD.

Interventions that target brain energy metabolism are also emerging as promising disease modifying therapy approaches for AD and for its prevention [6, 7]. Impaired brain bioenergetics precede symptomatic AD and are increasingly acknowledged as a contributor to its pathology [8]. Patients with AD exhibit dysfunction in the brain creatine (Cr) system [9], an integral system for maintaining brain energy flux. In the brain, free Cr is phosphorylated to form phosphocreatine (PCr), a primary means of storing and transporting high-energy phosphates derived from both cytosolic and mitochondrial metabolism [10]. In AD, the creatine kinase brain isoenzyme (BB-CK) responsible for phosphorylating Cr in the cytosol is severely reduced [11], as are both free Cr and PCr [12]. Impairments in the brain Cr system in AD may limit the ability to meet the high constant energy demand of the brain and potentially signal mitochondria to downregulate ATP production [13].

Creatine monohydrate (CrM) is an oral nutritional supplement that has been used extensively as an ergogenic aid for sport and exercise and has had growing interest in its possible brain health benefits [14]. It safely increases Cr levels in skeletal muscle [15], yet its effect on brain Cr levels has been inconsistent in the few small studies that have been completed with varying doses and durations [16,17,18,19,20,21]. In humans, limited but encouraging data suggest that CrM improves cognition in both younger and older adults [22], particularly in pathological brain conditions [23]. In animals, CrM supplementation has been shown to preserve bioenergetic function of hippocampal neurons and protect against brain aggregation of Aβ [24]. Recently, an 8-week CrM intervention in the 3xTg mouse model of AD improved hippocampal mitochondrial respiration in both male and female mice [25]. Female mice also improved cognition and decreased Aβ peptide aggregation in the hippocampus [25]. These data suggest that CrM improves the symptoms associated with AD in a mouse model.

Despite evidence in animal models that CrM may be neuroprotective, there have been no trials investigating CrM as a potential treatment in patients with AD. We are currently conducting a single-arm open-label pilot trial, Creatine to Augment Bioenergetics in Alzheimer’s disease (CABA), designed to investigate the feasibility of CrM supplementation and generate preliminary efficacy data pertaining to both function and mechanisms in the brain and periphery in patients with AD.

Study aims and objectives

The primary aim of CABA is to investigate whether 8 weeks of 20 g/day of CrM supplementation is feasible in patients with dementia due to AD. Our secondary aims are to generate preliminary data investigating changes in (1) total creatine concentration in the brain, (2) cognition, (3) mitochondrial biomarkers in the periphery and brain, and (4) muscle function and morphology coincident with the 8-week CrM intervention.

Design and method

The CABA protocol follows the guidelines for reporting non-randomized pilot and feasibility trials [26]. The study protocol has been approved by the Institutional Review Board at the University of Kansas Medical Center, and the trial has been registered with (NCT05383833).

Trial design

CABA is a single-arm, open-label, pre-post pilot trial. We will recruit 20 participants with AD, and all will be assigned to the 20 g/day CrM supplement intervention for 8 weeks. This dosage has been shown to be feasible and safe in healthy older adults, and limited data suggest that it may raise Cr levels in the brain [22].

Trial setting

CABA is a single-center trial at the University of Kansas Medical Center (KUMC) in Kansas City, KS. All study visits occur in person at the Hoglund Biomedical Imaging Center and the Landon Center on Aging, on campus buildings adjacent to each other in close proximity.

Sample size

The primary aim of CABA is to investigate the feasibility of the CrM intervention; thus, formal estimates of power are not required [27]. This is the first human trial to investigate CrM supplementation in patients with AD. The secondary aims of CABA are designed to generate means and confidence estimates that inform sample size requirements of subsequent studies. With a sample size of 20, we will be able to estimate an 80% compliance rate with a 95% confidence interval of 62.5–97.5% and establish effect estimates and confidence intervals that can be used to inform the design of future large clinical trials.

Participant eligibility criteria

The CABA trial aims to enroll an equal sample of males and females that have been diagnosed with cognitive impairment due to AD [28] with a mini-mental state exam (MMSE) score ≥ 17. Prior to enrollment, participants require stable dosage of AD-related medications (i.e., donepezil, memantine) for 30 days. Participants also require the cooperation of a study partner (spouse, relative, or close friend) to help facilitate the intervention and accompany the participant to all study visits. Table 1 summarizes the trial inclusion and exclusion criteria.

Table 1 Participant eligibility criteria


Recruitment for CABA leverages the existing recruitment infrastructure at the KU Alzheimer’s Disease Research Center (KU ADRC) [29]. The KU ADRC Outreach, Recruitment, and Engagement (ORE) Core initially pre-screens potential participants from a database of individuals that have consented to be contacted by the KU ADRC about study opportunities. Potential participants that meet preliminary diagnostic criteria are then phone screened by the CABA study team to explain the study and attain brief medical history. Individuals that are interested in participating in CABA and meet initial eligibility requirements are invited to attend the formal screening/baseline visit to attain informed consent and confirm eligibility. The CABA recruitment flow is illustrated in Fig. 1.

Fig. 1
figure 1

CABA recruitment and screening flow


Delivery of the intervention is facilitated by registered dietitians (RD). After all baseline assessments have been completed, RDs provide participants and their study partners with a 5-week supply of CrM powder (Life Extension, USA) along with written and verbal instruction on how to consume the CrM. Participants are instructed to stir 10 g (1 scoop) of CrM powder into liquid to consume in the midmorning and to repeat the same process in the evening for a total of 20 g each day. All participants receive another 5-week supply of CrM at the 4-week study visit, which provides enough CrM to each participant to complete the study. The additional week supply of CrM is intended to cover any error in study visit scheduling by 1 week (i.e., the 4-week visit at week 5 of intervention). Study partners are asked to assist participants in completion of a daily supplement calendar designed to track consumption of the two daily doses of CrM for the duration of the study. To encourage compliance and monitor for adverse events (AEs), the study RDs speak with participants and their study partners each week during planned telephone calls.

Study visits and assessment timeline

Study flow and a description of the study visits and procedures are presented in Table 2. All study procedures take place over five visits: one screening/baseline visit, a second baseline visit within 1 to 2 weeks of the first visit, a 4-week visit, and two 8-week visits that occur within 1 week of each other.

Table 2 Study visit procedure summary


All study assessments and their associated objectives are presented in Table 3.

Table 3 Study objectives and outcomes


The feasibility of the intervention will be based on compliance and safety. We also track the number of participants who are pre-screened for preliminary eligibility, contacted for recruitment, consent to enroll in the study, and withdraw from the study before or after allocation (Fig. 1).

The primary compliance measure will be based on participant completion of the study along with daily reported CrM intake on provided supplement calendars. Our criterion for compliance feasibility is constituted as ≥ 80% compliance with daily supplement intake among ≥ 80% of the study sample (n ≥ 16). Participants also bring the remainder of unconsumed CrM to 4-week and 8-week visits to be weighed by the study team to aid in determining compliance.


Safety is assessed by frequency and severity of reported AEs, proportion of participant withdrawals due to AEs, and monitoring of blood safety labs. Study personnel ascertain AEs and side effects during weekly telephone calls and at the 4-week and 8-week study visits. Participants also have continuous access to study personnel, which allows them to report potential AEs on a continuous basis. All AEs are immediately reported to the PI; assessed for severity, cause, and expectedness; and followed until resolution. Additional safety checks include monitoring change in lab values from a comprehensive metabolic panel and liver and renal function tests (Quest Diagnostics, USA).

Cognitive testing

The mini-mental state exam (MMSE), a brief, multidomain cognitive test and dementia screening tool, is administered by trained study personnel at baseline as part of the screening procedures and again at 8 weeks.

Comprehensive cognitive testing is also completed at baseline and 8 weeks using the NIH Toolbox® (NIH-TB) cognitive battery [30]. NIH-TB has been validated in both cognitively normal and demented older adults [31]. The cognitive battery is facilitated by trained staff on an iPad (Apple, USA) and contains individual tests from cognitive domains of attention, category switching, episodic memory, working memory, speed of processing, written language, and auditory language. Unadjusted, age‐adjusted, and fully adjusted (age, sex, education) scores are automatically calculated for each individual test as well as a composite cognition score.

Magnetic resonance imaging

High-resolution T1-weighted MRI is acquired using three-dimensional (3D) magnetization prepared rapid acquisition with gradient echo (MPRAGE) sequence (sagittal, 1 mm isotropic resolution, TE/TI/TR = 3.98/830/2000 ms, FOV = 256 × 256 mm2, 176 slices). The purpose of our T1-weighted MRI is to co-register magnetic resonance spectroscopy (MRS) scans and correct partial volume effects in MRS quantification.

Magnetic resonance spectroscopy

Brain total Cr (tCr), N-acetylaspartate (NAA), and glutathione (GSH) concentrations are measured via MRS at baseline and 8 weeks on a 3 T MR system (Skyra, Siemens, Erlangen, Germany) using a 20-channel receiver RF coil, selecting an axial slab of the frontal and parietal regions above the lateral ventricle. Measuring brain tCr will provide insight into the effectiveness of our CrM intervention to increase brain Cr concentration. GSH is an important antioxidant defense system that reflects oxidative stress status [32] and, together with NAA, will provide insight into brain mitochondrial integrity [33, 34]. Our semi-LASER MRSI sequence for Cr and NAA (TE/TR = 38/2000 ms, FOV = 20 cm, matrix = 14 × 14, slice thickness = 25 mm, VOI = 80 × 80 mm2) and doubly selective multiple quantum-filtered MRSI sequence for GSH (TE/TR = 115/1750 ms, FOV = 200 mm, matrix = 10 × 10, slice thickness = 25 mm) [35, 36] minimize the effect of MR system instability and subject motion during the scan [37]. Metabolite signals from the frontal, parietal, and frontoparietal regions are quantified with LCModel software using water signals from the same slab of the brain as an internal frequency and concentration reference [38]. Metabolite concentrations in the gray and white matter are also calculated using an established regression method [39].

Blood measures

Blood is drawn after an 8-h fast at baseline, 4-week, and 8-week study visits to perform several different assays.

At baseline, apolipoprotein E (APOE) genotype is determined using a TaqMan single-nucleotide polymorphism (SNP) allelic discrimination assay (ThermoFisher). APOE2, APOE3, and APOE4 alleles are determined using TaqMan probes at the two APOE-defining SNPs, rs429358 (C_3084793_20) and rs7412 (C_904973_10).

At baseline, 4 weeks, and 8 weeks, serum creatine is quantified via enzymatic assay (Quest Diagnostics). We expect serum creatine levels to increase as a result of the intervention, which can be used as an objective biomarker of compliance.

A comprehensive metabolic panel including liver and renal function tests (Quest Diagnostics) is measured at baseline and 8 weeks to monitor safety of the intervention.

Blood-based mitochondrial biomarkers are measured by the KU ADRC Biomarker Core at baseline and 8 weeks. Blood is collected into acid citrate dextrose tubes and fresh platelets, and lymphocytes are promptly isolated from the samples. Platelet and lymphocyte plasma membranes are permeabilized by adding digitonin, and the OROBOROS Oxygraph-2 k (OROBOROS Instruments, Austria) instrument is used to measure platelet and lymphocyte mitochondrial oxygen respiration kinetics. Reactive oxygen species (ROS) is measured using Amplex Red and MitoSOX with flow cytometry. ATP and ADP levels are measured using a bioluminescent assay.

Muscle function and morphology

Muscle function is assessed at baseline and 8 weeks using handgrip strength and leg extensor strength testing. Handgrip strength is measured as the average of three consecutive tests with a hand dynamometer (Lafayette Instrument, USA) while seated in a chair with feet resting on the floor. The study team verbally encourages participants to squeeze the dynamometer with maximal effort for at least 3 s. Leg extensor strength is measured by completing five maximal isokinetic contractions of the right leg extensors at three different velocities (1.05 rad·s−1, 2.09 rad·s−1, and 3.14 rad·s−1) on a calibrated isokinetic dynamometer (Biodex Medical Systems, Inc., USA) [40]. Study personnel verbally encourage participants to work as hard and as fast as possible during each repetition. Torque, position, and velocity signals from leg extensor strength testing are recorded.

Muscle morphology is assessed at baseline and 8 weeks using ultrasonography (GE Healthcare UK, UK) to measure muscle cross-sectional area (mCSA) and echo intensity (mEI) of the right quadriceps muscles, while participants lie supine. All ultrasound imaging analyses are performed using ImageJ software (Version 1.46r, National Institutes of Health, Bethesda, MD, USA).

Progression to a larger clinical trial

Meeting our primary feasibility goal of 80% compliance with the intervention protocol (n ≥ 16 participants that report consuming ≥ 80% of the CrM doses) will constitute a successful study, regarding feasibility. To support progression to a future randomized, controlled trial investigating differential effects of CrM and placebo on brain health outcomes in patients with AD will require both demonstration of feasibility and a positive signal from any of our secondary physiology or cognition outcomes. These measures were designed to generate preliminary data on symptoms and physiology that may be relevant to AD; thus, any changes associated with the CrM intervention would warrant broader, large-scale investigation.

Data analysis

Demographic characteristics of study participants will be presented as means and standard deviations for continuous variables and frequencies and proportions for categorical variables.

The aim of this study is to determine feasibility of the CrM intervention and outcomes assessments in patients with AD. Our primary outcome will be compliance, which we consider compliance with the intervention among 80% of the study sample to be satisfactory. We will also use our recruitment tracking pipeline to determine the length of time required to enroll our full sample, the proportion of interested participants that consented to enroll in the study, and the reasons for non-recruitment, non-enrollment, and non-compliance.

We will also explore preliminary data regarding change in several AD-related secondary outcomes. Since all participants receive the CrM intervention, we will conduct paired samples t-tests for all outcomes to estimate means and 95% confidence intervals of within-group change from baseline. If model assumptions are not met, we will alternatively use the nonparametric paired Wilcoxon test to report medians and interquartile ranges. Statistical analyses will be performed using R (v. 4.2.1; R Foundation, Vienna, Austria).

Data management and security

Data is collected both on paper and electronically. All paper data are stored securely in a locked filing cabinet at KUMC. All electronic data is managed using the Research Electronic Data Capture (REDCap) [41, 42] system hosted by a HIPAA-complaint server. Data is entered by the research staff and validated with real-time entry validation and offline validation by the investigators. The study team is assigned role-based access to REDCap which is protected by institutional multi-factor password protection.

All data is gathered for the explicit purposes of this study using procedures to ensure confidentiality. Within the REDCap database, participant identifiers are available to the study interventionalists only as they will be responsible for participant scheduling and delivery of the intervention. For all other study investigators, all data is de-identified and organized by participants’ assigned study IDs only. All data for publication or presentation will also be deidentified.


The results of this study will be published in peer-reviewed scientific journals and will be presented at international conferences, such as the Alzheimer’s Association’s International Conference. The research team will agree upon authorship in advance of manuscript submission. We will include statistical code used for data analyses as supplemental data with submitted manuscripts. Final de-identified data will available upon request to the principal investigator, contingent upon completion of a data sharing agreement with the University of Kansas Medical Center.


To date, the CABA study is the first to investigate CrM supplementation in patients with AD. Investigating CrM as an adjuvant therapy in AD is supported by recent positive animal studies and may influence several bioenergetic-related targets including mitochondrial function, oxidative stress, and inflammation. This pilot trial will provide information regarding the feasibility of the CrM intervention and the study outcomes, collectively, to inform the optimal design of a future clinical trial.

The CABA trial is not designed to determine efficacy of the CrM intervention in AD; thus, any results from its secondary outcomes should be interpreted with caution. The single-arm design of this study does not allow for comparison of change in secondary outcomes with a control group. This study also features a relatively small sample size along with measurement of several physiologic variables, which increases the chance for type I error due to multiplicity. However, since AD is a progressive disease, without intervention, we would expect either decline or no change in cognition from our participants. We also would not expect brain tCr levels or mitochondrial function to increase substantially with no intervention. Therefore, within-group signal for improvement in our secondary outcomes would provide further rationale for testing with larger studies. CABA is an important first step in generating effect estimates and confidence intervals to aid in determining the appropriate sample size necessary for hypothesis testing in a subsequent clinical trial.

Trial status

This manuscript reflects protocol version 2 dated March 17, 2023. Recruitment began in December 2022. We anticipate completion of all trial assessments by the end of June 2024.

Availability of data and materials

Not applicable. No datasets were generated or analyzed.



Alzheimer’s disease


Adverse event


Apolipoprotein E


Adenosine triphosphate


Creatine kinase brain isoenzyme


Body mass index


Creatine to Augment Bioenergetics in Alzheimer’s disease


Cerebral blood flow




Creatine monohydrate


Diet History Questionnaire III




Muscle cross-sectional area


Muscle echo intensity


Mini-mental state exam


Magnetic resonance imaging


Magnetic resonance spectroscopy




NIH Toolbox®




Total creatine


  1. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology. 2013;80(19):1778–83.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cummings J, Lee G, Nahed P, Kambar M, Zhong K, Fonseca J, Taghva K. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement (N Y). 2022;8(1):e12295.

    Article  PubMed  Google Scholar 

  3. Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RYK, Lannfelt L, Bradley H, Rabe M, Koyama A, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res Ther. 2021;13(1):80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016;537(7618):50–6.

    Article  ADS  CAS  PubMed  Google Scholar 

  5. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21.

    Article  PubMed  Google Scholar 

  6. Taylor MK, Swerdlow RH, Sullivan DK. Dietary neuroketotherapeutics for Alzheimer’s disease: an evidence update and the potential role for diet quality. Nutrients 2019;11(8).

  7. Taylor MK, Sullivan DK, Keller JE, Burns JM, Swerdlow RH. Potential for ketotherapies as amyloid-regulating treatment in individuals at risk for Alzheimer’s disease. Front Neurosci. 2022;16.

  8. Swerdlow RH. The Alzheimer’s disease mitochondrial cascade hypothesis: a current overview. J Alzheimers Dis. 2023.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hemmer W, Wallimann T. Functional aspects of creatine kinase in brain. Dev Neurosci. 1993;15(3–5):249–60.

    Article  CAS  PubMed  Google Scholar 

  10. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev. 2000;80(3):1107–213.

    Article  CAS  PubMed  Google Scholar 

  11. AliMohammadi M, Eshraghian M, Zarindast M-R, Aliaghaei A, Pishva H. Effects of creatine supplementation on learning, memory retrieval, and apoptosis in an experimental animal model of Alzheimer disease. Med J Islam Repub Iran. 2015;29:273.

    PubMed  PubMed Central  Google Scholar 

  12. Pettegrew JW, Panchalingam K, Klunk WE, McClure RJ, Muenz LR. Alterations of cerebral metabolism in probable Alzheimer’s disease: a preliminary study. Neurobiol Aging. 1994;15(1):117–32.

    Article  CAS  PubMed  Google Scholar 

  13. Walsh B, Tonkonogi M, Soderlund K, Hultman E, Saks V, Sahlin K. The role of phosphorylcreatine and creatine in the regulation of mitochondrial respiration in human skeletal muscle. J Physiol. 2001;537(Pt 3):971–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Prokopidis K, Giannos P, Triantafyllidis KK, Kechagias KS, Forbes SC, Candow DG. Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2023;81(4):416–27.

    Article  PubMed  Google Scholar 

  15. Kreider RB, Kalman DS, Antonio J, Ziegenfuss TN, Wildman R, Collins R, Candow DG, Kleiner SM, Almada AL, Lopez HL. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr. 2017;14:18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol. 1999;277(3):R698-704.

    Article  CAS  PubMed  Google Scholar 

  17. Lyoo IK, Kong SW, Sung SM, Hirashima F, Parow A, Hennen J, Cohen BM, Renshaw PF. Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. Psychiatry Res. 2003;123(2):87–100.

    Article  CAS  PubMed  Google Scholar 

  18. Pan JW, Takahashi K. Cerebral energetic effects of creatine supplementation in humans. Am J Physiol Regul Integr Comp Physiol. 2007;292(4):R1745–50.

    Article  CAS  PubMed  Google Scholar 

  19. Solis MY, Artioli GG, Otaduy MCG, Leite CDC, Arruda W, Veiga RR, Gualano B. Effect of age, diet, and tissue type on PCr response to creatine supplementation. J Appl Physiol (1985). 2017;123(2):407–14.

    Article  CAS  PubMed  Google Scholar 

  20. Merege-Filho CA, Otaduy MC, de Sa-Pinto AL, de Oliveira MO, de Souza GL, Hayashi AP, Roschel H, Pereira RM, Silva CA, Brucki SM, et al. Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study. Appl Physiol Nutr Metab. 2017;42(2):128–34.

    Article  CAS  PubMed  Google Scholar 

  21. Wilkinson ID, Mitchel N, Breivik S, Greenwood P, Griffiths PD, Winter EM, Van Beek EJ. Effects of creatine supplementation on cerebral white matter in competitive sportsmen. Clin J Sport Med. 2006;16(1):63–7.

    Article  PubMed  Google Scholar 

  22. Roschel H, Gualano B, Ostojic SM, Rawson ES. Creatine supplementation and brain health. Nutrients 2021;13(2).

  23. Dolan E, Gualano B, Rawson ES. Beyond muscle: the effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury. Eur J Sport Sci. 2019;19(1):1–14.

    Article  PubMed  Google Scholar 

  24. Brewer GJ, Wallimann TW. Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J Neurochem. 2000;74(5):1968–78.

    Article  CAS  PubMed  Google Scholar 

  25. Snow WM, Cadonic C, Cortes-Perez C, Adlimoghaddam A, Roy Chowdhury SK, Thomson E, Anozie A, Bernstein MJ, Gough K, Fernyhough P, et al. Sex-specific effects of chronic creatine supplementation on hippocampal-mediated spatial cognition in the 3xTg mouse model of Alzheimer’s disease. Nutrients. 2020;12(11).

  26. Lancaster GA, Thabane L. Guidelines for reporting non-randomised pilot and feasibility studies. Pilot Feasibility Stud. 2019;5:114.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, Robson R, Thabane M, Giangregorio L, Goldsmith CH. A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol. 2010;10:1.

    Article  PubMed  PubMed Central  Google Scholar 

  28. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263–9.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Vidoni ED, Bothwell RJ, Burns JM, Dwyer JR. Novel recruitment models will drive Alzheimer’s trial success. Alzheimers Dement. 2018;14(1):117–9.

    Article  PubMed  Google Scholar 

  30. Weintraub S, Dikmen SS, Heaton RK, Tulsky DS, Zelazo PD, Bauer PJ, Carlozzi NE, Slotkin J, Blitz D, Wallner-Allen K, et al. Cognition assessment using the NIH toolbox. Neurology. 2013;80(11 Suppl 3):S54-64.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hackett K, Krikorian R, Giovannetti T, Melendez-Cabrero J, Rahman A, Caesar EE, Chen JL, Hristov H, Seifan A, Mosconi L, et al. Utility of the NIH toolbox for assessment of prodromal Alzheimer’s disease and dementia. Alzheimers Dement (Amst). 2018;10:764–72.

    Article  PubMed  Google Scholar 

  32. Wilkins HM, Harris JL, Carl SM, E L, Lu J, Eva Selfridge J, Roy N, Hutfles L, Koppel S, Morris J, et al. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum Mol Genet 2014;23(24):6528–41.

  33. Clark JB. N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci. 1998;20(4–5):271–6.

    Article  CAS  PubMed  Google Scholar 

  34. Moffett JR, Arun P, Ariyannur PS, Namboodiri AM. N-acetylaspartate reductions in brain injury: impact on post-injury neuroenergetics, lipid synthesis, and protein acetylation. Front Neuroenergetics. 2013;5:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Choi IY, Lee SP, Denney DR, Lynch SG. Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T. Mult Scler. 2011;17(3):289–96.

    Article  CAS  PubMed  Google Scholar 

  36. Choi IY, Lee P. Doubly selective multiple quantum chemical shift imaging and T(1) relaxation time measurement of glutathione (GSH) in the human brain in vivo. NMR Biomed. 2013;26(1):28–34.

    Article  CAS  PubMed  Google Scholar 

  37. Lee CY, Choi IY, Lee P. Prospective frequency correction using outer volume suppression-localized navigator for MR spectroscopy and spectroscopic imaging. Magn Reson Med. 2018;80(6):2366–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30(6):672–9.

    Article  CAS  PubMed  Google Scholar 

  39. Choi IY, Lee SP, Merkle H, Shen J. In vivo detection of gray and white matter differences in GABA concentration in the human brain. Neuroimage. 2006;33(1):85–93.

    Article  PubMed  Google Scholar 

  40. Herda TJ, Ryan ED, Kohlmeier M, Trevino MA, Gerstner GR, Roelofs EJ. Examination of muscle morphology and neuromuscular function in normal weight and overfat children aged 7–10 years. Scand J Med Sci Sports. 2018;28(11):2310–21.

    Article  PubMed  Google Scholar 

  41. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research Electronic Data Capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81.

    Article  PubMed  Google Scholar 

  42. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, McLeod L, Delacqua G, Delacqua F, Kirby J, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95: 103208.

    Article  PubMed  PubMed Central  Google Scholar 

Download references


This research is supported by the Alzheimer’s Association (AARG-22–924314) and the National Institutes of Health (K01 AG065487 and P30 AG072973). Creatine monohydrate used in this trial was donated by Life Extension, Inc. Additional support is provided by the University of Kansas Medical Center Department of Dietetics and Nutrition. The project funders and sponsor did not have any role in the design or report of this protocol.

Author information

Authors and Affiliations



All authors were involved in the development of the trial protocol. MKT wrote the first draft of the manuscript. All authors provided edits and approved the final manuscript. MKT is the principal investigator of the study. All other authors are listed in alphabetical order by surname.

Corresponding author

Correspondence to Matthew K. Taylor.

Ethics declarations

Ethics approval and consent to participate

The study protocol has been approved by the Institutional Review Board at the University of Kansas Medical Center. Informed consent is obtained from all participants prior to participating in this study. Participants also have the option to consent to storage of collected biological specimens for use in future ancillary studies. All protocol modifications will be approved by the investigators and submitted to the Institutional Review Board at the University of Kansas Medical Center for approval. All active participants will be re-consented with updated consent forms reflecting protocol changes.

Consent for publication

Not applicable.

Competing interests

M. K. T. receives research support from the National Institutes of Health (NIH) and the Alzheimer’s Association. In the past 2 years, J. M. B. has received research support from the NIH; research support to conduct clinical trials (paid to institution) from Eli Lilly, Amylyx Pharmaceuticals, Biogen, AbbVie, Astra-Zeneca, and Roche; and has served as a consultant for Renew Research, Amylyx Pharmaceuticals, Eisai, and Eli Lilly. I. Y. C. receives research support from the NIH and the US Highbush Blueberry Council. T. J. H. receives support from the National Strength and Conditioning Association. P. L. receives research support from the NIH. A. N. S. declares no competing interests. D. K. S. receives research support from the NIH, the Egg Nutrition Center, and the US Highbush Blueberry Council. R. H. S. receives research support from the NIH. H. M. W. receives research support from the NIH and the Alzheimer’s Association.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Taylor, M.K., Burns, J.M., Choi, IY. et al. Protocol for a single-arm, pilot trial of creatine monohydrate supplementation in patients with Alzheimer’s disease. Pilot Feasibility Stud 10, 42 (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: