Neurodegeneration [Stroke and Alzheimer disease (AD)] is fastly becoming one of the leading causes of age-associated disability, dementia, and death. In addition, the Centers for Disease Control and Prevention (CDC) and the National Center for Health Statistics recently reported that AD has surpassed diabetes as a leading cause of death and is now considered the sixth-leading cause of death in the United States. Unfortunately, currently no effective treatments are available against this devastating disease. In the past we have shown the preservation and improvement of cognitive tasks in depressed and demented patients after 24 and 36 months of combined pharmacological and non- pharmacological treatment. Here we present the results of our ongoing, naturalistic study, in the same outpatient setting, at the 60 month follow up. The study group consisted of 156 medically ill, physically-disabled patients with mild to moderate dementia and depression. Patients were treated with antidepressants, cholinesterase inhibitors, and NMDA antagonists, along with their regular medication regimen. Non-pharmacological intervention was centered on a home-based program of physical and cognitive exercises as well as with vitamins and supplements (multivitamins, vitamin E, L-methylfolate, alpha-lipoic acid, acetyl-l-carnitine, omega-3, and coenzyme Q-10) and diet modification. Cognitive assessments were performed yearly. After 60 months of treatment, performance of all tasks remained at or above baseline. The MMSE, Cognistat–Attention, Cognistat–Judgment, and RFFT - Total Unique Designs demonstrated significant improvement. Our results, for the first time, demonstrate arrest in cognitive decline in demented/depressed patients with multiple medical co-morbidities for 60 months. Future investigations addressing the application of a combined, integrative treatment models in clinical practices are warranted.