The cognitive effects of creatine supplementation in older adults and preclinical models of dementia: A scoping review.

BACKGROUND & OBJECTIVES: Dementia represents a growing global health crisis, yet disease-modifying therapies remain limited. Impaired brain energy metabolism, neuroinflammation, and synaptic dysfunction are some shared pathological features across dementia subtypes that may be amenable to metabolic intervention. Creatine supplementation, through its role in the phosphocreatine/ATP buffering system and proposed neuroprotective properties, has attracted growing scientific and public interest as a candidate intervention for dementia. This scoping review maps the existing evidence on creatine supplementation and dementia-related cognitive outcomes, with attention to intervention characteristics including dose, duration, formulation, route of administration as well as the characteristics of preclinical models.

METHODS: Following the Joanna Briggs Institute (JBI) methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, a systematic search of PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted. No date restrictions were applied to the search; eligibility was limited to English-language reports. Studies were eligible if they evaluated creatine supplementation in older adults or preclinical animal models with dementia and reported at least one cognitive outcome.

RESULTS: From 8317 records identified and screened, six studies reported across seven publications, met eligibility criteria comprising one in vitro study, four in vivo animal model studies, and one human pilot trial resulting in two publications. No relevant randomized controlled trials (RCTs) were identified in the search. Evidence was heterogeneous across study design, population, and intervention characteristics. Preclinical studies demonstrated predominantly neuroprotective effects through bioenergetic support and neuroinflammatory modulation, though one rodent study reported worsening spatial memory. A single human pilot trial (n = 20) found that high-dose supplementation (20 g/day for 8 weeks) increased brain total creatine by 11% and was associated with improved fluid cognition. Sex-specific effects were identified in one rodent study, with female animals demonstrating cognitive benefit and males showing a trend toward harm. This was paralleled by sex-divergent bioenergetic responses in the human trial.

CONCLUSION: Current evidence for creatine supplementation in dementia is limited, heterogeneous, and predominantly preclinical. While not supporting a causal inference, preliminary human data does suggest biological plausibility and feasibility, supporting the need for adequately powered, sex-stratified randomized controlled trials in adults with dementia. While preclinical data support a mechanistic rationale for its use, this review identifies critical gaps including the absence of any controlled clinical trials, limited understanding of optimal dosing for brain penetrance, and the need to prospectively examine sex as a biological moderator of treatment response.