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Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin\u2010converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pT<jats:sup>308<\/jats:sup>AKT1\/total AKT1, but not with pS<jats:sup>307<\/jats:sup>IRS\u20101\/total IRS\u20101 or the density of cells stained positive for pS<jats:sup>616<\/jats:sup> IRS\u20101. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau\u2010neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Late\u2010life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52132","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T05:55:39Z","timestamp":1719899739000},"page":"2112-2122","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Associations of renin\u2013angiotensin system inhibitor use with brain insulin signaling and neuropathology"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9821-5928","authenticated-orcid":false,"given":"Han","family":"Tong","sequence":"first","affiliation":[{"name":"Rush Alzheimer's Disease Center 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