Vagus Nerve Stimulation as a Potential Therapy in Early Alzheimer's Disease: A Review

Abstract

Cognitive dysfunction in Alzheimer's disease (AD) is caused by disturbances in neuronal circuits of the brain underpinned by synapse loss, neuronal dysfunction and neuronal death. Amyloid beta and tau protein cause these pathological changes and enhance neuroinflammation, which in turn modifies disease progression and severity. Vagal nerve stimulation (VNS), via activation of the locus coeruleus (LC), results in the release of catecholamines in the hippocampus and neocortex, which can enhance synaptic plasticity and reduce inflammatory signalling. Vagal nerve stimulation has shown promise to enhance cognitive ability in animal models. Research in rodents has shown that VNS can have positive effects on basal synaptic function and synaptic plasticity, tune inflammatory signalling, and limit the accumulation of amyloid plaques. Research in humans with invasive and non-invasive VNS devices has shown promise for the modulation of cognition. However, the direct stimulation of the vagus nerve afforded with the invasive procedure carries surgical risks. In contrast, non-invasive VNS has the potential to be a broadly available therapy to manage cognitive symptoms in early AD, however, the magnitude and specificity of its effects remains to be elucidated, and the non-inferiority of the effects of non-invasive VNS as compared with invasive VNS still needs to be established. Ongoing clinical trials with healthy individuals and patients with early AD will provide valuable information to clarify the potential benefits of non-invasive VNS in cognition and AD. Whether invasive or non-invasive VNS can produce a significant improvement on memory function and whether its effects can modify the progression of AD will require further investigation.

Keywords: Alzheimer; MCI; memory; noradrenaline; norepinepherine; plasticity; vagal; vagus.

FIGURE 1

Vagus nerve afferent activity causes catecholamine release from the locus coeruleus into widespread brain regions. These include areas relevant for memory and highly impacted in Alzheimer’s disease such as the hippocampus. Norepinephrine (NE) acts on astrocytes and neuroglia, influencing an anti-inflammatory profile and neurotrophic support for neurons. NE also acts directly on neuronal populations to modulate synaptic plasticity and function with distinct effects depending on brain regions and neuron sub-types. LC activation also causes release of dopamine in the hippocampus which modulates neuronal plasticity and excitability and has a role in the consolidation of “everyday” type memory.