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In mid to late life, it has been identified as a risk factor for Alzheimer\u2019s disease (AD) with evidence that depression might be an early manifestation of AD. Although the underlying mechanisms by which depression enhances AD development remain unknown, there are several features commonly seen in both diseases such as the presence of neuroinflammation. In this study, we aimed to identify whether neuroinflammation is increased in depression as observed in the early stages of AD by examining post-mortem human brain tissue. Post-mortem human brain tissue from 54 cases with depression and 37 controls without depression were retrieved from the Douglas Bell Canada Brain Bank. Sixteen early-stage AD cases defined as a Braak stage III-IV and 15 controls were sourced from the South West Dementia Brain Bank. Frozen tissue from the dorsal prefrontal cortex was obtained for all cases in order to measure inflammatory proteins (IFN-\u03b3, IL-1\u03b2, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-\u03b1) and endothelial markers (ICAM-1, VCAM) using ELISA and MesoScale Multiplex Assays. In the depression group, increase of IL-6 and IL-10, and decrease of IL-1\u03b2 were observed compared to controls, with no changes detected for the other cytokines and the endothelial markers. In early-stage AD cases, only increased ICAM-1 expression was found compared to controls, indicating endothelial activation as an early feature of AD. None of the cytokines measured showed alteration of their expression in early-stage AD cases. Depression, but not AD, was associated with evidence of neuroinflammation. Depression may increase AD risk through different mechanism(s) than inflammation.<\/jats:p>","DOI":"10.1371\/journal.pone.0320561","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T19:18:23Z","timestamp":1743707903000},"page":"e0320561","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Depression as a risk factor for Alzheimer\u2019s disease: A human post-mortem study"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6741-9370","authenticated-orcid":true,"given":"Mizuki","family":"Morisaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farnoosh","family":"Rezaali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie C.","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Boche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Golam M.","family":"Khandaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Turecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey I.","family":"Sinclair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"issue":"1","key":"pone.0320561.ref001","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1590\/1516-4446-2016-2107","article-title":"Depression and psychodynamic psychotherapy","volume":"40","author":"\u00c2 Ribeiro","year":"2017","journal-title":"Revista Brasileira de Psiquiatria"},{"key":"pone.0320561.ref002","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association. 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