Multimodal Neuroimaging Mechanisms of Apathy in Alzheimer's Disease: A Narrative Review of Structural, Functional,...

Apathy is the most common neuropsychiatric symptom in Alzheimer's disease (AD) and is conceptualized as a pathological reduction of goal-directed motivation and behavior. It is currently believed that apathy has an independent neurobiological basis rather than merely accompanying cognitive decline. This narrative review synthesizes evidence from structural, functional, and molecular neuroimaging studies published up to 2025, identified through targeted PubMed searches and reference tracking, without applying formal systematic inclusion/exclusion criteria. Existing imaging evidence indicates that the core mechanism of apathy lies in the specific impairment of the prefrontal-basal ganglia motivational circuit: gray matter atrophy and hypometabolism in the anterior cingulate cortex (ACC) and orbitofrontal cortex are closely associated with impaired motivation integration and reward evaluation, whereas structural damage to the dorsolateral prefrontal cortex contributes to executive planning deficits. Functional network analysis further reveals suppression of the default mode network and ineffective compensation of the central executive network. Molecular imaging studies confirm that structural degeneration of the locus coeruleus, dopaminergic presynaptic transmission dysfunction, and synergistic pathological accumulation of amyloid-beta and Tau proteins in the motivational circuit collectively constitute the neurobiological basis of apathy. Furthermore, computational modeling has already been employed as an analytical framework to dissect these mechanisms, revealing altered effort-based decision-making and abnormal frontoparietal connectivity. Given the frequent impairment in self-awareness (anosognosia) regarding their own apathy in AD, informant-based assessments are essential for accurate clinical evaluation. Ultimately, integrating these multimodal biomarkers may facilitate early identification and stratified interventions, including dopaminergic and noradrenergic pharmacotherapies as well as non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS).