Objective: This study aims to assess the role of mental-orientation in the diagnosis of mild cognitive impairment and Alzheimer’s disease using a novel task. Method: A behavioral study (Experiment 1) compared the mental-orientation task to standard neuropsychological tests in patients across the Alzheimer’s disease spectrum. A functional MRI study (Experiment 2) in young adults compared activations evoked by the mental-orientation and standard-orientation tasks as well as their overlap with brain regions susceptible to Alzheimer’s disease pathology. Results: The mental-orientation task differentiated mild cognitively impaired and healthy controls at 95% accuracy, while the Addenbrooke’s Cognitive Examination, Mini-Mental State Examination and standard-orientation achieved 74%, 70% and 50% accuracy, respectively. Functional MRI revealed the mental-orientation task to preferentially recruit brain regions exhibiting early Alzheimer’s-related atrophy, unlike the standard-orientation test. Conclusions: Mental-orientation is suggested to play a key role in Alzheimer’s disease, and consequently in early detection and follow-up of patients along the Alzheimer’s disease spectrum.