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Degenerative and compensatory changes in the locus coeruleus\u2013noradrenergic (LC\u2013NA) system have been implicated in agitation in Alzheimer's disease. However, substantial interindividual variability in the emergence of agitation over the course of dementia suggests that neuropathological changes alone are unlikely to fully account for individual differences in susceptibility to agitation. We explore how mentalizing capacity (the ability to understand one's own and others\u2019 thoughts, feelings, beliefs, and intentions) in both care recipients and caregivers may influence agitation propensity. Mentalizing supports adaptive emotion regulation and may underpin person\u2010centered care, but becomes less effective under conditions of heightened arousal and interpersonal stress. It is proposed that LC\u2013NA regulation of arousal may influence the capacity to sustain mentalizing under stress, potentially contributing to agitation and increasing the likelihood of escalation of care. Notably, mentalizing may be compromised by different processes in care recipients and caregivers. In care recipients, neurodegeneration may impair mentalizing, potentially in part through dysregulation of the LC\u2013NA system. In caregivers, distress, burden, and emotionally challenging interactions may undermine the capacity to maintain mentalizing. As disease progression is likely to increasingly constrain mentalizing capacity in care recipients, we consider pharmacological modulation of care recipients\u2019 LC\u2013NA function and psychosocial interventions to strengthen caregiver mentalizing as complementary and potentially modifiable targets for intervention. This conceptualization is best understood within a relationship\u2010centered care perspective, which extends beyond person\u2010centered care by emphasizing care as embedded in the dynamic relationships between caregivers and care recipients, rather than focusing solely on individual patient preferences. Taken together, these considerations inform a neurorelational framework for understanding and addressing agitation, integrating neurobiological and socio\u2010emotional perspectives to provide a basis for personalized intervention approaches to potentially mitigate the effects of neurodegeneration on \u201cneuropsychiatric reserve.\u201d<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70333","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T10:01:25Z","timestamp":1791972085000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Advancing therapeutic approaches for agitation: A neurorelational perspective"],"prefix":"10.1002","volume":"12","author":[{"given":"Kathy Y.","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Psychiatry University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Salaminios","sequence":"additional","affiliation":[{"name":"Research Department of Clinical, Educational and Health Psychology University College London  London UK"},{"name":"Research Department British Association of Counselling and Psychotherapy  Lutterworth UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Mather","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology University of Southern California  Los Angeles California USA"},{"name":"Department of Psychology University of Southern California  Los Angeles California USA"},{"name":"Department of Biomedical Engineering University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Howard","sequence":"additional","affiliation":[{"name":"Division of Psychiatry University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1017\/S1041610214001963","article-title":"Agitation in cognitive disorders: international psychogeriatric association provisional consensus clinical and research definition","volume":"27","author":"Cummings J","year":"2015","journal-title":"Int Psychogeriatr"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2018-022260","article-title":"How do care home staff understand, manage and respond to agitation in people with dementia? 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