A Scoping Review of Creatine Supplementation in Alzheimer’s Disease: Evidence from Preclinical and Clinical Studies

Background/Objectives: Although creatine supplementation has a theoretical rationale for neuroprotection, public interest has outpaced available scientific evidence. Alzheimer’s disease (AD), a major and growing global health concern, is among the neurodegenerative diseases proposed to benefit from creatine supplementation. This scoping review systematically maps the existing literature on creatine supplementation for AD to identify gaps that limit translational progress. Methods: Following JBI methodology and PRISMA-ScR guidelines, a search in five electronic databases was conducted for preclinical and clinical studies evaluating creatine interventions in AD. The methodological quality of the studies was appraised using the SYRCLE and NIH tools, respectively. Results: Nine unique studies were included. The preclinical models investigated neuron apoptosis, oxidative stress, neuroinflammation, mitochondrial function, cognitive outcomes, and pathophysiological clearance. Conversely, clinical studies were limited to a pilot trial that suggested preliminary tolerability but could not establish causality. This review identifies six limitations within the current evidence: (1) a reliance on acute or non-transgenic animal models that lack construct validity; (2) a need to address sexual dimorphism; (3) a lack of studies exploring administration routes to bypass the blood–brain barrier; (4) a complete lack of independent randomized controlled trials (RCTs), with all clinical evidence originating from a single research group; (5) an absence of research assessing creatine as a preventive strategy; and (6) a shortage of assessment regarding physical syndromes, such as frailty. Conclusions: The scientific evidence for creatine in AD remains preliminary. Future research should prioritize progressive transgenic models, evaluate noninvasive administration routes, investigate effects on frailty, assess long-term preventive efficacy, account for sex as a variable, and transition to rigorous RCTs.