Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate

•What is the primary question addressed by this study?—Methylphenidate treatment has shown encouraging results in initial trials of apathy in Alzheimer's disease; however, its neurobiologic rationale remains unclear.•What is the main finding of this study?—We propose that the degeneration of the prefrontal cortex in Alzheimer's disease produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.•What is the meaning of the finding?—Understanding the neuronal circuits subserving motivated behavior and their reliance on catecholamine actions provides a rationale for methylphenidate in the treatment of apathy in patients with Alzheimer's disease. The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%–70% of persons with AD. Previous attempts to treat apathy in AD—both nonpharmacologically and pharmacologically—have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex—dorsolateral, orbital-ventromedial, and dorsomedial—helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.