Vagus Nerve Stimulation in Alzheimer's Disease and Mild Cognitive Impairment: Current Evidence and Future Directions.

Vagus nerve stimulation (VNS) may improve cognition and promote underlying brain health through various mechanisms including the noradrenaline and cholinergic pathways. Whilst early human studies used invasive devices (iVNS), recent decades have seen the emergence of non-invasive devices that stimulate the vagus nerve transcutaneously (tVNS) via either the cervical branches in the neck (tcVNS) or the auricular branch in the ear (taVNS). With this increase in more accessible devices, tVNS is gaining interest as a novel therapy in mild cognitive impairment (MCI) and Alzheimer's disease (AD). This targeted review aims to understand the current evidence in human trials in this specific population. PubMed, Cochrane, EMBASE, MEDLINE, and Google Scholar were searched. Six human interventional studies were found (one iVNS; five taVNS). VNS is well tolerated and study designs demonstrate feasibility within this population for future blinded and appropriately powered long-term studies with participants applying tVNS at home. However, protocols and tVNS settings remain variable. Working memory domains such as verbal fluency and 3D processing show the most promise but global cognitive scores were also sensitive in some cases. The role of biomarkers of tVNS activity and its effect on AD markers and neuroinflammation should be considered in the design of future studies.