BACKGROUND: This longitudinal study addressed whether mindfulness practice prevents psychological and behavioral symptoms, especially mood disorders, in Alzheimer's disease (AD). OBJECTIVE: To assess the incidence of depression in the course of AD and to determine which non-pharmacological treatment (NPT) is most effective in preventing psychopathological symptoms. METHODS: We conducted a longitudinal, non-inferiority and equivalence randomized clinical trial, repeated-measures design, with a control group and three experimental treatments: mindfulness, cognitive stimulation, and relaxation. Each experimental group performed three weekly sessions for two years. The pharmacological treatment of all participants was donepezil (10 mg). Participants were patients with probable AD without diagnosed depression from the public neurology services of the Canary Health Service, Spain. Psychological evaluation was performed using the Geriatric Depression Scale (GDS), Hamilton Depression Rating Scale (HDRS), and Neuropsychiatric Inventory (NPI-Q). The statistical analysis included only patients who attended at least 75% of the sessions. A nonparametric, repeated-measures analysis was performed with Kruskal-Wallis H test and between-group differences with Mann-Whitney U test with Bonferroni correction (p < 0.008). Effect size was calculated with partial eta-squared. RESULTS: The results showed significant differences with large effect sizes (η2p>0.14) between mindfulness and the rest of the experimental groups as well as the control in the GDS, HDRS, and NPI-Q scales. CONCLUSION: Compared to the other experimental groups, only mindfulness prevented the onset of depression and other psychopathologies in early-stage AD. Based on its effectiveness in maintaining cognitive functions and preventing psychopathology, we recommend mindfulness as the first-choice NPT for mild to moderate AD.