The emerging field of non-invasive brain stimulation in Alzheimer's disease

Treating cognitive impairment is a holy grail of modern clinical neuroscience. In the past few years, non-invasive brain stimulation is increasingly emerging as a therapeutic approach to ameliorate performance in patients with cognitive impairment and as an augmentation approach in persons whose cognitive performance is within normal limits. In patients with Alzheimer's disease, better understanding of brain connectivity and function has allowed for the development of different non-invasive brain stimulation protocols. Recent studies have shown that transcranial stimulation methods enhancing brain plasticity with several modalities have beneficial effects on cognitive functions. Amelioration has been shown in preclinical studies on behaviour of transgenic mouse models for Alzheimer's pathology and in clinical studies with variable severity of cognitive impairment. While the field is still grappling with issues related to the standardization of target population, frequency, intensity, treatment duration and stimulated region, positive outcomes have been reported on cognitive functions and on markers of brain pathology. Here we review the most encouraging protocols based on repetitive transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation, visual-auditory stimulation, photobiomodulation and transcranial focused ultrasound, which have demonstrated efficacy to enhance cognitive functions or slow cognitive decline in patients with Alzheimer's disease. Beneficial non-invasive brain stimulation effects on cognitive functions are associated with the modulation of specific brain networks. The most promising results have been obtained targeting key hubs of higher-level cognitive networks, such as the frontal-parietal network and the default mode network. The personalization of stimulation parameters according to individual brain features sheds new light on optimizing non-invasive brain stimulation protocols for future applications.