Pain in Alzheimer’s Disease: Disrupted Multilevel Integration of Nociception, Affective Processing and Clinical Expression Across Clinical and Preclinical Evidence

Pain is a multidimensional experience arising from the integration of nociceptive signals with affective, cognitive and behavioral processes. In Alzheimer’s disease (AD), pain assessment remains challenging, as reduced self-reported pain is frequently observed despite exposure to potentially painful conditions, suggesting altered processing rather than its absence. Emerging evidence indicates that pain in AD is characterized by a disruption of coordination among sensory detection, affective experience and clinical expression. Within this framework, nociceptive input may remain partially preserved, while its integration into emotionally meaningful and behaviorally coherent responses is compromised. Clinical studies report reduced self-report alongside observable indicators of discomfort, including agitation, withdrawal and affective disturbances. In parallel, preclinical models demonstrate preserved reflexive responses but altered affective-motivational processing. These alterations are associated with neuroinflammatory processes, synaptic dysfunction, large-scale network disconnection and changes in neuromodulatory systems involved in affective pain regulation, ultimately disrupting the integration of nociceptive signals within limbic and cortical networks. Taken together, this review integrates clinical and preclinical evidence to characterize pain in AD as a disruption of multilevel integration linking nociception, affective processing and clinical expression, with important implications for pain assessment strategies that extend beyond self-report to incorporate behavioral and translational approaches.