Tier 4 — mechanistic

Eight weeks of creatine monohydrate supplementation is associated with increased muscle strength and size in Alzheimer's disease: data from a single-arm pilot study

Aaron N. Smith, Debra K. Sullivan, Jill K. Morris, Aaron F. Carbuhn, Trent J. Herda, Matthew K. Taylor
Frontiers in Nutrition 2025 Volume 12, Article 1670641

Bibliography

PubMed
PMID 40977987
PubMed Central
PMC12443791
DOI
10.3389/fnut.2025.1670641
Video explainer
Watch on YouTube Biohack Blueprint's video walkthrough of this study.
Funding
This research was supported by the Alzheimer's Association (AARG-22-924314), the National Institutes of Health (K01 AG065487 and P30 AG072973), and the National Center for Advancing Translational Sciences of the National Institutes of Health (TL1TR00236 and UL1TR002366). The University of Kansas Medical Center Department of Dietetics and Nutrition provided additional support. Life Extension Inc. donated the creatine monohydrate powder.
Competing interests
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Study snapshot

DesignSingle-arm pilot trial.
ModelHuman patients with a clinical diagnosis of probable Alzheimer's disease-dementia.
Samplen=20 participants
Intervention20 g/day of creatine monohydrate powder, divided into two 10-gram doses.
Duration8 weeks.
EndpointsPrimary outcomes assessed were feasibility, muscle strength (handgrip and leg), muscle size/morphology, and neuromuscular junction integrity.

What the study showed, in plain terms

The loss of physical function is common in Alzheimer's disease (AD), often presenting as diminished muscle mass and strength which limits mobility and promotes frailty. Creatine monohydrate is a widely studied supplement that increases energy availability in skeletal muscle and has strong evidence for improving muscle strength and size in older adults. This pilot study aimed to test whether eight weeks of creatine supplementation could provide similar skeletal muscle benefits specifically for patients with AD.

In this single-arm trial, 20 older adults diagnosed with probable AD-dementia consumed 20 grams of creatine monohydrate daily for eight weeks. Throughout the study, researchers measured the participants' upper body strength using handgrip dynamometry and lower body strength using leg dynamometry. They also used ultrasound imaging to track changes in the cross-sectional area and thickness of specific leg muscles, alongside blood tests to measure a biomarker for neuromuscular junction integrity.

After the eight-week period, the participants exhibited modest but statistically significant improvements in both their handgrip strength and the cross-sectional area of the rectus femoris and vastus medialis thigh muscles. Additionally, there was a localized decrease in subcutaneous fat thickness in two of the thigh regions. The study did not find significant changes in lower leg strength, overall body composition, or the neuromuscular junction biomarker. The researchers concluded that creatine is a well-tolerated intervention that may help preserve muscle function in AD patients, though larger, placebo-controlled trials are needed to confirm these early findings.

Key findings

  • Following 8 weeks of supplementation, mean handgrip strength significantly increased by 1.9 kg (from a baseline of 33.5 ± 11.6 kg to 35.4 ± 11.5 kg, p=0.02).
  • Muscle cross-sectional area (mCSA) significantly increased in the rectus femoris (7.6 ± 2.5 cm² vs. 7.8 ± 2.7 cm², p=0.03) and the vastus medialis (10.1 ± 3.0 cm² vs. 10.2 ± 3.1 cm², p=0.01).
  • Subcutaneous fat significantly decreased in the rectus femoris region (1.09 ± 0.6 cm vs. 1.05 ± 0.6 cm, p=0.006) and vastus lateralis region (0.99 ± 0.6 cm vs. 0.95 ± 0.5 cm, p=0.003).
  • No significant changes were detected in lower leg peak torque across any of the three tested velocities (1.05 rad·s⁻¹, 2.10 rad·s⁻¹, 3.14 rad·s⁻¹) among the subset of ten participants who completed leg dynamometry.
  • Muscle thickness did not significantly change in the rectus femoris (p=0.41), vastus medialis (p=0.37), or vastus lateralis (p=0.17).
  • Plasma C-terminal agrin fragment (CAF) concentrations, serving as a biomarker of neuromuscular junction integrity, did not significantly change (2.5 ± 0.6 ng/mL vs. 2.6 ± 0.8 ng/mL, p=0.46).
  • Overall anthropometrics, including BMI (p=0.25), percent lean body mass (p=0.10), and waist circumference (p=0.20), showed no significant changes from baseline.

What this study can and cannot tell us

As a single-arm pilot study, this trial lacked a placebo control group, meaning the results must be interpreted cautiously as preliminary, hypothesis-generating findings rather than definitive clinical evidence. The study featured a small sample size (n=20) with limited racial and sex diversity, and the eight-week duration may have been too brief to observe meaningful changes in more complex physiological markers like neuromuscular junction remodeling.

Additionally, methodological limitations impacted the lower-body strength assessments. Mechanical issues with the leg dynamometer reduced the sample size for that specific test to only ten participants and prevented the use of standardized familiarization trials. The lack of familiarization trials may have resulted in an underestimation of true strength or the introduction of learning effects.

Finally, the ultrasonography assessments were conducted without standardized participant hydration protocols, which can influence measurements of muscle cross-sectional area and thickness, and were performed without assessor blinding, potentially introducing measurement bias.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability