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. 2025 May 19;11(2):e70101.
doi: 10.1002/trc2.70101. eCollection 2025 Apr-Jun.

Creatine monohydrate pilot in Alzheimer's: Feasibility, brain creatine, and cognition

Aaron N Smith  1 , In-Young Choi  2   3   4   5 , Phil Lee  2   3   4   5 , Debra K Sullivan  1   6   7   8 , Jeffrey M Burns  2   6 , Russell H Swerdlow  2   5   6   9 , Emma Kelly  1 , Matthew K Taylor  1   6
Affiliations

Creatine monohydrate pilot in Alzheimer's: Feasibility, brain creatine, and cognition

Aaron N Smith et al. Alzheimers Dement (N Y). .

Abstract

Background: Preclinical studies suggest that creatine monohydrate (CrM) improves cognition and Alzheimer's disease (AD) biomarkers. However, there is currently no clinical evidence demonstrating the effects of CrM in patients with AD.

Methods: In this single-arm pilot trial, we investigated the feasibility of 20 g/day CrM for 8 weeks in 20 patients with AD. We measured compliance throughout; serum creatine at baseline, 4 weeks, and 8 weeks; and brain total creatine (tCr) and cognition (National Institutes of Health [NIH] Toolbox, Mini-Mental State Examination [MMSE]) at baseline and 8 weeks.

Results: Nineteen participants achieved the target of ≥80% compliance with the CrM intervention. Serum Cr was elevated at 4 and 8 weeks (p < .001) and brain tCr increased by 11% (p < .001). Cognition improved on global (p = .02) and fluid (p = .004) composites, List Sorting (p = .001), Oral Reading (p < .001), and Flanker (p = .05) tests.

Discussion: Our data suggest that CrM supplementation is feasible in AD and provides preliminary evidence for future efficacy and mechanism studies.

Trial registration: ClinicalTrials.gov, NCT05383833, registered on May 20, 2022.

Highlights: Creatine monohydrate supplementation was feasible in patients with Alzheimer's disease.Creatine monohydrate was associated with increased brain total creatine.Creatine monohydrate was associated with improvements in cognition.Efficacy of creatine monohydrate in Alzheimer's disease should be studied further.

Keywords: Alzheimer's disease; bioenergetics; brain creatine; cognition; creatine monohydrate; magnetic resonance spectroscopy; pilot trial.

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Conflict of interest statement

A.N.S. receives research support from the National Institutes of Health (NIH). I.Y.C. receives research support from the NIH and the US Highbush Blueberry Council. P.L. receives research support from the NIH. 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. R.H.S. receives research support from NIH and Astra‐Zeneca; he has served as a consultant for Nestle Health Science, ADmit Therapeutics, and Apellis Pharmaceuticals. D.K.S. receives research support from the NIH and the U.S. Highbush Blueberry Council. E.K. reports no disclosures. M.K.T. receives research support from the NIH, Alzheimer's Association, and the Avocado Nutrition Center.

Figures

FIGURE 1
FIGURE 1
Creatine to Augment Bioenergetics in Alzheimer's (CABA) compliance measures. (A) Dot plot illustrating individual self‐reported compliance with the intervention from daily CrM compliance trackers. The red dotted line indicates the 80% compliance threshold for protocol adherence. (B) Bar plots with error bars (mean ± standard error) comparing serum Cr values from baseline to 4 weeks and 8 weeks. Due to missing serum Cr values, the total sample size is n = 16 across all conditions. **p < .01; ***p < .001; CrM, creatine monohydrate; Cr, creatine.
FIGURE 2
FIGURE 2
Change in brain total Cr after 8 weeks of CrM supplementation. Brain Cr was quantified using ¹H MRS. Boxplots display Cr values at baseline and after 8 weeks, with individual changes overlaid. Solid green lines represent male participants, whereas dashed gray lines represent female participants. ***p < .001. Cr, creatine; MRS, magnetic resonance spectroscopy; IU, international units.
FIGURE 3
FIGURE 3
Change in cognitive measures after 8 weeks of creatine monohydrate supplementation. All scores were derived with the NIH Toolbox cognitive battery. Boxplots display values at baseline and 8 weeks, with individual changes overlaid. Solid green lines represent male participants, whereas dashed gray lines represent female participants. **p < .01; ***p < .001.
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