Neurobiological links between Alzheimer's disease and reward system dysfunction

Alzheimer's disease (AD) is a highly prevalent progressive neurodegenerative disorder with unclear etiology, complex symptoms, and limited treatment options. Early pathological processes in AD emerge long before the onset of overt cognitive and motor symptoms and involve the accumulation of amyloid-β oligomers and neurofibrillary tangles, accompanied by neuroinflammation and neuronal loss. Importantly, the brain reward system comprises cortical and subcortical structures that share neurochemical pathways and reciprocal connectivity with regions affected during AD progression. Consistent with this overlap, reward-related behavioral deficits, including apathy, anhedonia, and motivational impairments, are frequently observed in both patients with AD and experimental models of the disease. Here, we discuss the neuroanatomical, neurochemical, and molecular overlap between AD pathology and reward-related neural circuits and propose that dysfunction of the reward system may represent an important pathogenetic endophenotype of AD. A better understanding of these multilevel interactions may help refine the conceptual framework of AD and support the development of novel therapeutic strategies targeting reward-related circuits and their underlying molecular mechanisms.