Randomized clinical trial, comparative and single blind aims to determine effects on cognition, psychological and behavioral symptoms and functionality of 5 Hz repetitive transcranial magnetic stimulation (rTMS) administered over left dorsolateral prefrontal cortex (lDLPFC) compared to six regions protocol, divided in two sub-conditions: day 1 (Broca area, Wernicke area and lDLPFC) alternated by day 2 (left and right parietal association cortex, and right dorsolateral prefrontal cortex [rDLPFC]). Main outcomes will be evaluated at ending of 15 rTMS sessions and 4 weeks after.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline that affects behavior and daily functionality. Its etiology is unknown and treatment efficacy is partial. Repetitive transcranial magnetic stimulation has been suggested as a potential treatment as of several trials has revealed improvements in language, episodic memory, psychological and behavioral symptoms in dementia as well as functionality using different experimental designs, stimulation parameters and cortical targets comparisons. However, it remains to determine the most effective modality, comparing outcomes with cortical targets poorly studied and how much the effects last. The main objective of this study is to determine which of two stimulation modalities provides a better cognitive and behavioral effect also on functionality in patients with potential diagnosis of AD, administered over lDLPFC (Condition A) and a six areas condition (Condition B) in which are alternated two sub-conditions (Day 1: Broca and Wernicke areas and lDLPFC, and Day 2: bilateral parietal association cortex and rDLPFC) along 15 sessions and 1500 pulses per session.

For this purpose, will be randomized 22 patients with potential diagnosis of AD (according to DSM-5) to both stimulation conditions (11 patients to each condition). The rTMS will be administered at 5 Hz and 1500 pulses per session (30 trains and 10 seconds inter-train interval) along 15 sessions with a post-treatment evaluation at 4 weeks comparing: time response, post-treatment effects and 4 weeks effects.

To evaluate clinical response among stimulation conditions will be used Alzheimer´s Disease Assessment Scale COGNITIVE (ADAS-cog), Cumming's Neuropsychiatric Inventory (NPI), Yesavage Geriatric Depression Scale (GDS), Interview for Deterioration-in-daily Living Activities in Dementia (IDDD) and Clinical Global Impression (CGI). The modified version of Mini Mental State (MMSE-FOLSTEIN) will be applied in the same time points of other evaluations also at the session 5 and 10. Other interest variables are: age, sex, civil status, education, occupation, time and type of pharmacological treatment.

Inclusion Criteria:

• Patients with file number at National Institute of Psychiatry "Ramón de la Fuente Muñiz".
• Scholarship of at least 5 years or above.
• Dementia diagnosis established by clinical examination made by their responsible physician, according the Diagnose Criteria for Alzheimer Disease for possible, mild or moderate according to DSM-5. Severity will be stratified with Mini-Mental State (MMSE-FOLSTEIN): as a) mild: 21-26 and b) moderated 15-20 points; in addition, with Reisberg Global Deterioration, the states from 2 to 4 that correspond a cognitive deficit mild and moderated.
• In the case of concomitant treatment with memantine or acetylcholinesterase inhibitors, the patient should have taken it for at least 6 months prior to study.
• In the case of other pharmacological treatments for psychiatric conditions, for example, antidepressants, anxiolytic or antipsychotics, the patient should have taken stable doses for at least 2 months.
• Patients with another no-psychiatric comorbidity should be stable (according to diagnostic criteria and supported by laboratory studies or metric assessments).
• Every patient should have a caregiver (for example, spouse, a relative or a professional caregiver) along the study who could stay with the patient at least 10 hours/week.
• Signing of informed consent by patient and caregiver.
• Patients and caregivers who can attend in weekdays, along three weeks assessments and treatment sessions at National Institute of Psychiatry "Ramón de la Fuente Muñiz".

Exclusion Criteria:

• Patients with severe agitation symptoms or difficulties to cooperate with the study.
• Patients with history of epilepsy.
• Patients with sudden onset of apoplexy, focal neurologic findings as hemiparesis, sensory loss, visual field deficit and lack of coordination in the legs in early stages of disease.
• Convulsion or walking disorder at onset or very early stages of the disease.
• Patients with history of severe psychiatric disorders.
• Patients with alterations in a conventional electroencephalogram (paroxysmal phenomena identified by a specialized clinical neurophysiologist).
• Patients with pacemaker or implanted metallic intracranial objects.

Elimination criteria:

• Decision of patient or caregiver to left the study.
• Modification in doses or pharmacological treatment prior to start the study.
• Patients with new clinical findings and who require complementary pharmacological treatment.
• Presence of adverse events that could affect health and could limit maintain the patient in treatment.
• Exacerbation of cognitive or behavioral symptoms during the study.

Single Blind (Investigator)