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Many depressed, older adults fail to respond to first line antidepressant treatment, experience relapse and exhibit persistent symptoms, including anxiety, apathy and cognitive impairment, that may reflect underlying neurodegenerative processes. Advances in molecular imaging, particularly positron emission tomography (PET) allow direct in-vivo investigation of neurobiological mechanisms underlying late-life depression symptom trajectories, treatment response and the potential links to neurodegenerative disease. Molecular imaging studies in late-life depression\u00a0have revealed alterations across neurotransmitter systems\u00a0and Alzheimer\u2019s disease pathology\u00a0(beta-amyloid and Tau)\u00a0and a potential role of neuroinflammation. In\u00a0late-life depression,\u00a0variability in symptom presentation and treatment response\u00a0arises from interacting neurotransmitter, inflammatory, and neurodegenerative processes and potentially other molecular mechanisms\u00a0that impair synaptic plasticity. Future directions include the application of next-generation PET tracers targeting glutamatergic signaling, mitochondrial function, histone deacetylase activity, and cell-type\u2013specific inflammation, along with multi-modal image analysis methods to test mechanistic models\u00a0. Molecular imaging holds significant promise for guiding the development of targeted, mechanism-based treatments that reduce the burden of late-life depression and its associated vulnerability to neurodegenerative disease.<\/jats:p>","DOI":"10.1038\/s41386-026-02340-2","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T16:13:44Z","timestamp":1775060024000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Trajectories of late-life depression: insights from molecular imaging"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4929-1932","authenticated-orcid":false,"given":"Sophie E.","family":"Holmes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0706-5440","authenticated-orcid":false,"given":"Gwenn S.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"2340_CR1","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1001\/jama.278.14.1186","volume":"278","author":"BD Lebowitz","year":"1997","unstructured":"Lebowitz BD. 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