Neuronutraceuticals for Alzheimer's Disease Treatment: A Systematic Review of Randomised Controlled Trials Over the Last 20 Years

Alzheimer's disease (AD) remains the leading cause of dementia, and with current treatments offering limited efficacy, interest in neuronutraceuticals has grown due to their potential to target core mechanisms of AD pathology. This PROSPERO‐registered systematic review, conducted per PRISMA guidelines, screened 4684 manuscripts and included 37 randomised controlled trials (RCTs) evaluating neuronutraceuticals across the AD continuum. Trials ranged from Phase 1 to Phase 3 and investigated compounds acting on amyloid and tau pathology (e.g., DHA and tramiprosate), neuroinflammation (resveratrol, curcumin), hormonal modulation (soy isoflavones), synaptogenesis (bryostatin‐1, magnesium), oxidative stress (Ginkgo biloba, alpha‐lipoic acid), energy metabolism (oxaloacetate, NAD + , spirulina), synaptic plasticity (Fortasyn Connect, cerebrolysin) and cholinergic transmission (crocin, huperzine‐A). Although three agents showed favourable outcomes in large‐scale RCTs, sodium oligomannate was excluded due to design limitations, and genistein and Ginkgo biloba were dismissed based on neutral findings in other trials. Most studies were underpowered or inconclusive, and Cochrane RoB2 assessment revealed ‘some concerns’ in all but two trials, primarily due to attrition (86.5%) and reporting bias (81%). Overall, current evidence does not support the clinical implementation of neuronutraceuticals in AD, underscoring the need for larger, methodologically rigorous trials to clarify their therapeutic role. Trial Registration The research protocol was registered with PROSPERO (CRD420251127545)