Despite advances in the treatment of Alzheimer’s disease (AD), there is currently no prospect of a cure, and evidence shows that multifactorial interventions can benefit patients. A promising therapeutic alternative is the use of transcranial direct current stimulation (tDCS) simultaneously with cognitive intervention. The combination of these non-pharmacological techniques is apparently a safe and accessible approach. This study protocol aims to compare the efficacy of tDCS and cognitive intervention in a double-blind, randomized and factorial clinical trial. One hundred participants diagnosed with mild-stage AD will be randomized to receive both tDCS and cognitive intervention, tDCS, cognitive intervention, or placebo. The treatment will last 8 weeks, with a 12-month follow-up. The primary outcome will be the improvement of global cognitive functions, evaluated by the AD Assessment Scale, cognitive subscale (ADAS-Cog). The secondary outcomes will include measures of functional, affective, and behavioral components, as well as a neurophysiological marker (Brain-derived neurotrophic factor, BDNF). This study will enable us to assess, both in the short and long term, whether tDCS is more effective than the placebo and to examine the effects of combined therapy (tDCS and cognitive intervention) and isolated treatments (tDCS vs. cognitive intervention) on patients with AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02772185—May 5, 2016.

Background Dementia is among the most common chronic noncommunicable neurodegenerative diseases. In the long term, it causes disability and loss of autonomy and independence. It is estimated that there are 35.6 million people with Alzheimer’s disease worldwide. Several clinical aspects of this disease have been widely studied, but the main focus of study has been memory loss, which is one of the first symptoms. The present study proposes an innovative intervention that combines cognitive training and multisite transcranial direct current stimulation, which interferes with other clinical aspects of the subject. Case presentation In this study, we present two subjects diagnosed with mild Alzheimer’s disease. Subject 1 is an 82-year-old Brazilian Latin American woman with a high school education who was diagnosed with Alzheimer’s disease 8 years ago and uses an Exelon patch. Subject 2 is an 88-year-old Brazilian Latin American woman with an incomplete primary education who was diagnosed with Alzheimer’s disease 1 year ago and received medical orientation to temporarily discontinue medications for Alzheimer’s disease. Both participants were subjected to intermittent cognitive training sessions and concomitant transcranial stimulation in three weekly 30-minute sessions in which a brain area was stimulated every 10 minutes for a total of 24 sessions, with a 2-month follow-up. Transcranial stimulation was applied to six different regions of the cortex: the dorsolateral prefrontal cortex bilaterally, the somatosensory association cortex bilaterally and Broca’s and Wernicke’s areas. Comparing the results of tests performed before and after the treatment period, a 1-point improvement was observed for both subjects on the Word Recall task of the Alzheimer Disease Assessment Scale, which evaluates symptoms related to the decline of episodic memory. Improvement in the executive functions domain was also observed through the results of the Stroop test, Victoria version. Conclusions The results from the two presented cases show that multisite transcranial stimulation associated with cognitive training is an effective adjuvant method for the treatment of patients diagnosed with mild Alzheimer’s disease. Its effects can benefit patients’ daily routines by reducing cognitive deficits by keeping intact areas active and/or compensating for lost functions. Trial registration NCT02772185. Registered 13 May 2016, http://www.clinicaltrials.gov/ct2/show/NCT02772185. Retrospectively registered.

A Doença de Alzheimer (DA) é uma desordem neurodegenerativa progressiva, com apresentação de declínio das funções cognitivas e, consequentemente, perda gradual da autonomia, de acordo com a evolução da doença. O objetivo do presente estudo foi avaliar os efeitos da técnica de Estimulação Transcraniana por Corrente Contínua (ETCC) associada ao Treino Cognitivo (COG) nos domínios cognitivos responsáveis pela Linguagem e Praxia em sujeitos que se encontram na fase leve da DA. Trata-se de um estudo tipo relato de caso com 2 sujeitos, em que ambos foram submetidos ao protocolo de intervenção de ETCC e COG aplicados simultaneamente. Foi realizada uma análise descritiva dos resultados obtidos através dos subtestes do ADAS-Cog (Nomeação de objetos e dedos, Compreensão de ordens, Capacidade construtiva, Praxia ideativa, Linguagem oral, Dificuldade em encontrar palavras em um discurso espontâneo, Compreensão da linguagem oral), do Teste de Fluência Verbal (FAS) e do Teste de Figuras Sobrepostas de Poppelreuter aplicados nos períodos pré e pós-tratamento que avaliaram os domínios estudados no presente trabalho. Após realizado o protocolo de intervenção, observou-se melhora significativa no desempenho dos sujeitos por meio dos instrumentos de avaliação utilizados. A abordagem terapêutica empregada mostrou-se um método eficaz para o tratamento da DA na fase leve, atuando na manutenção e preservação das funções cognitivas dos sujeitos.Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder, presenting a decline in cognitive functions and, consequently, a gradual loss of autonomy, according to the evolution of the disease. The objective of the present study was to evaluate the effects of the Transcranial Direct Current Stimulation (tDCS) technique associated with Cognitive Training (COG) in the cognitive domains responsible for Language and Praxis in subjects who are in the light phase of AD. This is a case-report study with 2 subjects, in which both were submitted to the tDCS and COG intervention protocol applied simultaneously. A descriptive analysis of the results obtained through ADAS-Cog subtests (Naming of objects and fingers, Order comprehension, Constructive capacity, Praxis ideal, Oral language, Difficulty finding words in a spontaneous speech, Understanding of oral language), The Verbal Fluency Test (FAS) and the Poppelreuter Overlap Test applied in the pre- and post-treatment periods that evaluated the domains studied in the present study. After the intervention protocol, a significant improvement in the performance of the subjects was observed through the evaluation instruments used. The therapeutic approach employed was an effective method for the treatment of AD in the light phase, acting in the maintenance and preservation of the cognitive functions of the subjects.Keywords: Alzheimer's disease, Transcranial Direct Current Stimulation, Cognitive Training, Language, Praxis.Resumen La enfermedad de Alzheimer (DA) es un desorden neurodegenerativo progresivo, con una presentación de declive de las funciones cognitivas y, consecuentemente, pérdida gradual de la autonomía, de acuerdo con la evolución de la enfermedad. El objetivo del presente estudio fue evaluar los efectos de la técnica de Estimulación Transcraniana por Corriente Continua (ETCC) asociada al Entrenamiento Cognitivo (COG) en los dominios cognitivos responsables del Lenguaje y Praxia en sujetos que se encuentran en la fase leve de la DA. Se trata de un estudio tipo relato de caso con 2 sujetos, en que ambos fueron sometidos al protocolo de intervención de ETCC y COG aplicados simultáneamente. Se realizó un análisis descriptivo de los resultados obtenidos a través de los subtítulos del ADAS-Cog (Nombramiento de objetos y dedos, Comprensión de órdenes, Capacidad constructiva, Praxia ideativa, Lenguaje oral, Dificultad en encontrar palabras en un discurso espontáneo, Comprensión del lenguaje oral), de la Prueba de Fluencia Verbal (FAS) y del Prueba de Figuras superpuestas de Poppelreuter aplicadas en los períodos pre y post-tratamiento que evaluaron los dominios estudiados en el presente trabajo. Después de realizado el protocolo de intervención, se observó una mejora significativa en el desempeño de los sujetos por medio de los instrumentos de evaluación utilizados. El abordaje terapéutico empleada se mostró un método eficaz para el tratamiento de la DA en la fase leve, actuando en el mantenimiento y preservación de las funciones cognitivas de los sujetos.Palabras clave: Enfermedad de Alzheimer, Estimulación Transcraniana por Corriente Continua, Entrenamiento Cognitivo, Lenguaje, Praxia.