The Emergence of Neuropsychiatric Symptoms in Preclinical Alzheimer’s Disease: an Emotion Regulation Perspective

Preclinical Alzheimer’s disease (AD) is associated with distressing neuropsychiatric symptoms (NPSs) that may accelerate progression toward dementia. Existing approaches probe the symptom-level domain-general or domain-specific neural correlates of NPSs. However, the field lacks process-oriented models of symptom emergence for targeted treatment. We propose one pathway for symptom emergence involving the disruption of emotion regulation (ER) systems by early AD pathology. AD pathology in the ventral anterior cingulate cortex-ventromedial prefrontal cortex disrupts model-free ER that modulates negative valuations using experience-dependent reinforcement learning (e.g., fear extinction), leading to increased negative valuations and negative affect. We further propose that model-based ER competes for overtaxed executive resources and is less successful in preclinical AD, particularly in demanding real-world contexts. These changes lead to a shift toward negative affect, leading to divergent trajectories of NPSs depending on critical moderators. We discuss implications for intervention to improve NPSs and potentially slow dementia progression.