Background: Alzheimer's disease is a major health problem in our society. To date, pharmacological treatments to reduce Alzheimer's disease symptoms have obtained poor results and there is a growing interest in finding non-pharmacological treatments for this impactful disease. Transcranial Magnetic Stimulation is a non-invasive tool which can induce changes in brain activity and long term modifications of impaired neural networks, and therefore holds promise as a clinical intervention.

Our overall goal is to study the benefit of targeting Transcranial Magnetic Stimulation based on the individual's unique functional connectivity (personalized targeting) instead of current non-individualized approaches. Specifically, the intermittent Theta Burst protocol will be used and changes in cognitive, functional, and emotional deficits in these patients will be evaluated. Functional brain connectivity changes induced by the TMS treatment will be also assessed.

Methods: A double blind randomized controlled trial will be conducted to assess the effects of TMS treatment immediately, one month, three months and six months after the end of the treatment in comparison to the baseline measurements. Forty-five patients with a diagnosis of Alzheimer's disease, will be randomly allocated (1:1:1) into experimental (active Transcranial Magnetic Stimulation), sham control group, or conventional intervention control group. Neuropsychological, functional, and emotional assessment will be conducted, as well as functional connectivity measures, in order to assess the effectiveness of the treatment.

Discussion: The investigators expect to demonstrate that personalized Transcranial Magnetic Stimulation intervention has measurable positive impact in cognitive and emotional functioning, functionality, and brain connectivity, thus representing a potential treatment for Alzheimer's disease.

Inclusion Criteria:

• Diagnosis of Alzheimer's disease according to the diagnostic criteria of the National Institute on Ageing and the Alzheimer's Association
• Ages between 60 and 75 years
• Mini Mental State Examination score between 20 and 26
• Global Deterioration Scale score of 3 or 4
• Functional independence for basic daily life activities (part C of the Blessed Scale equal or 0)
• Rosen Ischemia Scale less or equal to 4
• Able to read and write
• Stable medical and pharmacological state during the 3 consecutive months immediately before the start of the study
• Computed Tomography Scan and Magnetic Resonance Imaging in the last 12 months previous to the selection, compatible with the diagnosis of probable Alzheimer's disease in the subjects diagnosed
• Absence of clinically significant anomalies in the medical history or clinical laboratory results during the selection
• Screening analyses within normal range with the objective of detecting and excluding other causes of dementia in the last 12 months previous to selection. Laboratory values required in order to be considered within the normal range are as follows: complete blood count, thyroid hormones, T4, folic acid, vitamin B12, albumin, transaminase alanine, amino-transferase aspartate, gamma-glutamic transferase, sodium, potassium, urea, creatinine, glucose while fasting
• Being treated by Acetylcholinesterase Inhibitors
• Signed consent form, previously approved by the Research Ethics Committee

Exclusion Criteria:

• Knowledge of Spanish or Catalan after the age of 15
• Less than 4 years of schooling
• Intellectual deficiency (Premorbid Intelligence Quotient, vocabulary, less than 85)
• Not controlled medical conditions or severe mental disorders that may affect the Central Nervous System, including signs of increased intracranial pressure or intracranial lesions
• Presenting one or more vascular risks
• Medical conditions not controlled that may cause medical emergencies in case the produce convulsions (expel: cardiac malformations, cardiac arrhythmias, asthma, etc.)
• Medical history of convulsions, previous diagnosis of epilepsy, previous registry of abnormal electroencephalogram or family history of epilepsy
• Severe hearing problems or ringing in the ears (tinnitus)
• Severe loss of visual acuity
• Moderate or severe depression according to a score >11 (moderate depression) or 19 (severe depression) in the Geriatric Depression Scale
• Presence of tremors or motor control of the dominant upper extremity
• Being under pharmacological treatment with medications indicated in the security guidelines.
• Drug or alcohol consumption or history of abuse in the last 24 months prior to the study
• Implants of metal pieces in the brain (excluding dental fillings)
• Either of the following medical devices: pacemaker, implanted medication pumps, vagal nerve stimulators, deep cerebral stimulators, transcutaneous electrical stimulation units, ventriculus-peritoneal derivations, titanium plates, cochlear implants, aneurysm clips, etc…
• Negative response towards new technology
• Existence of any situation that may cause the subject, according to the principal researcher, not be an adequate candidate for the study