Cortico–Cortical Paired Associative Stimulation (ccPAS) in Ageing and Alzheimer’s Disease: A Quali-Quantitative Approach to Potential Therapeutic Mechanisms and Applications

Background/Objectives: Cognitive decline and Alzheimer’s disease (AD) pose a major challenge for the ageing population, with impaired synaptic plasticity playing a central role in their pathophysiology. This article explores the hypothesis that cortico–cortical paired associative stimulation (ccPAS), a non-invasive brain stimulation technique, can restore synaptic function by targeting impaired spike-timing-dependent plasticity (STDP), a key mechanism disrupted in AD. Methods: We reviewed existing studies investigating the effects of ccPAS on neuroplasticity in both ageing and AD populations. Results: Findings suggest age-specific effects, with ccPAS improving motor performance in young adults but showing limited efficacy in older adults, likely due to age-related declines in synaptic plasticity and cortical excitability. In AD, ccPAS studies reveal significant impairments in long-term potentiation (LTP)-like plasticity, while long-term depression (LTD)-like mechanisms appear relatively preserved, emphasising the need for targeted neuromodulation approaches. Conclusions: Despite promising preliminary results, evidence remains limited and largely focused on motor function, with the impact of ccPAS on cognitive domains still underexplored. To bridge this gap, future research should focus on larger and more diverse cohorts to optimise ccPAS protocols for ageing and AD populations and investigate its potential for enhancing cognitive function. By refining stimulation parameters and integrating neuroimageing-based personalisation strategies, ccPAS may represent a novel therapeutic approach for mitigating neuroplasticity deficits in ageing and neurodegenerative conditions.