Four-Limb Coordinated Training and Neuroplasticity in Older Adults with Cognitive Frailty: Mechanisms and Clinical Evidence.

Cognitive frailty (CF), the coexistence of physical frailty and cognitive impairment without dementia, is associated with disability, institutionalization, and mortality, yet exercise prescriptions for this syndrome remain insufficiently targeted. This review examined whether four-limb coordinated training, defined as exercise that combines integrated upper- and lower-limb movement with meaningful coordination or motor-cognitive demands, is associated with neuroplasticity-related and clinical benefits in older adults with CF. Following PRISMA 2020 guidance, we conducted a focused PubMed-based systematic search and included six controlled studies for qualitative synthesis. Because interventions, comparators, and outcomes were highly heterogeneous, results were synthesized narratively using a tiered framework covering direct neuroplasticity outcomes, mechanistic proxy biomarkers, and indirect clinical outcomes. Across Baduanjin, virtual reality motor-cognitive training, exergaming, and functional resistance exercise, the direction of effect was generally favorable for global cognition, executive-related outcomes, frailty status, and physical performance including gait, balance, and chair-rise function. Direct mechanistic evidence was limited but suggested possible improvements in cerebral hemodynamics and hippocampal subregion structure, while biomarker studies indicated reductions in oxidative stress and inflammatory burden. Taken together, current evidence suggests that four-limb coordinated training is a biologically plausible and clinically relevant intervention candidate for CF, but confidence remains limited by the single-database search, small samples, study heterogeneity, indirect mechanistic endpoints, and short follow-up. The distinctive contribution of this review is the integration of intervention classification with a cautious neuroplasticity framework that can guide future trials toward standardized definitions, better reporting of coordination complexity and dose, and multimodal mechanistic assessment.