Modulators of Gamma tACS in Alzheimer's Disease (Mod-GammAD)

Brain oscillations are ubiquitous in the human brain and have been implicated in cognitive and behavioral states defined in precisely tuned neural networks. In neurodegenerative disorders, neurodegeneration is accompanied by changes in oscillatory activity leading to the emerging concept of neurological and psychiatric disorders as "oscillopathies". Alzheimer's disease, which accounts for the vast majority of age-related dementias, is characterised by a prominent disruption of oscillations in the gamma frequency band. The restoration of gamma oscillations by neural entrainment in animal models of Alzheimer's disease have shown a remarkable decrease in the pathological burden of amyloid and tau via increased microglial activity, resulting in a significant increase of cognitive performances.

Transcranial alternating current brain stimulation (tACS), is a neurophysiological method of non-invasive modulation of the excitability of the central nervous system that is having an increasingly numerous spectrum of potential therapeutic applications. Recent studies have demonstrated the effectiveness of this method in modulating the natural frequencies of cerebral oscillation, underlying multiple cognitive processes such as verbal memory, perception and working memory. On the basis of these premises, the treatment with gamma tACS is proposed in patients affected by Alzheimer's disease.

In this randomized, double-blind, sham-controlled, cross-over study, the investigators will evaluate the modulators of response on cognitive measure to a single stimulation with gamma tACS on the posterior parietal cortex in patients with Mild Cognitive Impairment due to Alzheimer's disease.

Brain oscillations are ubiquitous in the human brain and have been implicated in cognitive and behavioral states defined in precisely tuned neural networks. In neurodegenerative disorders, neurodegeneration is accompanied by changes in oscillatory activity leading to the emerging concept of neurological and psychiatric disorders as "oscillopathies". Alzheimer's disease, which accounts for the vast majority of age-related dementias, is characterised by a prominent disruption of oscillations in the gamma frequency band. The restoration of gamma oscillations by neural entrainment in animal models of Alzheimer's disease have shown a remarkable decrease in the pathological burden of amyloid and tau via increased microglial activity, resulting in a significant increase of cognitive performances.

Transcranial alternating current brain stimulation (tACS), is a neurophysiological method of non-invasive modulation of the excitability of the central nervous system that is having an increasingly numerous spectrum of potential therapeutic applications. Recent studies have demonstrated the effectiveness of this method in modulating the natural frequencies of cerebral oscillation, underlying multiple cognitive processes such as verbal memory, perception and working memory.

On the basis of these premises, the treatment with gamma tACS is proposed in patients affected by Alzheimer's disease.

In this randomized, double-blind, sham-controlled, cross-over study, the investigators will evaluate the modulators of response on cognitive measure to a single stimulation with gamma tACS on the posterior parietal cortex in patients with Mild Cognitive Impairment due to Alzheimer's disease.

Subjects will be randomized in two groups, one receiving a single treatment with gamma tACS (40 Hz) first and the other receiving sham stimulation. After one week the treatments will be exchanged. Patients will be evaluated with neuropsychological tests and neurophysiological measures of cholinergic transmission. Modulators of response, including cognitive reserve, baseline impairment, apo-E genotype, MRI measures of atrophy and connectivity, electric field modelling, will be considered.

Eligibility Criteria:
Inclusion Criteria:

- Mild Cognitive Impairment due to Alzheimer's disease (according to Albert et al., Alzheimers Dement 2011).

Exclusion Criteria:

* Cerebrovascular disorders, previous stroke, hydrocephalus, and intra-cranial mass documented by MRI.
* History of traumatic brain injury or other neurological diseases.
* Serious medical illness other than AD
* History of seizures
* Pregnancy
* Metal implants in the head (except dental fillings)
* Electronic implants (i.e. pace-maker, implanted medical pump)
* Age \<18 years