{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:47:48Z","timestamp":1792802868812,"version":"4.5.0"},"reference-count":47,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Antihypertensive medications that stimulate angiotensin II type 2 or 4 receptors (angiotensin II\u2013stimulating medications) may be associated with lower risk of dementia.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To examine associations between cumulative exposure to angiotensin II\u2013stimulating vs angiotensin II\u2013inhibiting antihypertensive medications and neuropathology, accounting for blood pressure.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This community-based autopsy cohort study from the Adult Changes in Thought cohort was conducted at Kaiser Permanente Washington between February 24, 1994, and November 25, 2022, among 756 participants who had blood pressure measurements and at least 1 person-year (PY) of angiotensin II\u2013stimulating or \u2013inhibiting antihypertensive medication exposure prior to death. Statistical analysis was performed between September 2024 and August 2025.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n Angiotensin II\u2013stimulating antihypertensive medications (angiotensin II receptor blockers, dihydropyridine calcium channel blockers, thiazides) and angiotensin II\u2013inhibiting antihypertensive medications (angiotensin-converting enzyme inhibitors, \u03b2-blockers, nondihydropyridine calcium channel blockers) were ascertained from paper-based medical records (before 1977) and electronic prescription fill data (after 1977). The primary exposure was cumulative angiotensin II PYs, and the secondary exposure was long-term use (\u226515 years).<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Neuropathology outcomes were classified as Alzheimer disease related, vascular brain injury, or other. Exploratory outcomes included quantitative measures of A\u03b242 and phosphorylated tau. Data were analyzed using multivariable modified Poisson, proportional odds, and linear regression models and accounted for potential selection bias.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n The sample included 756 participants (mean [SD] age at death, 89.2 [6.4] years; 440 women [58.2%]; mean [SD] follow-up, 22.2 [13.5] years). Compared with exposure to 5 additional PYs of angiotensin II\u2013inhibiting antihypertensive medications, exposure to 5 additional PYs of angiotensin II\u2013stimulating antihypertensive medications was associated with a 6% lower risk for arteriolosclerosis (relative risk [RR], 0.94; 95% CI, 0.89-0.99), with long-term use associated with a 24% lower risk (RR, 0.76; 95% CI, 0.63-0.91). For exploratory outcomes, PYs of angiotensin II\u2013stimulating antihypertensive medications were associated with less quantitative phosphorylated tau burden in several brain regions (temporal lobe [adjusted ratio of geometric means, 0.79; 95% CI, 0.62-1.00], hippocampus [adjusted ratio of geometric means, 0.83; 95% CI, 0.71-0.97], cornu ammonis subfield 1 [adjusted ratio of geometric means, 0.86; 95% CI, 0.74-0.99], and transentorhinal cortex [adjusted ratio of geometric means, 0.83; 95% CI, 0.70-0.98]) but not with A\u03b242 quantitative measures.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this community-based autopsy cohort study, angiotensin II\u2013stimulating antihypertensive medications were associated with lower risk of neuropathological burden, supporting findings from epidemiologic dementia studies. Additional mechanistic research examining the effects of individual antihypertensive classes on Alzheimer disease\u2013related biomarkers is warranted.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.59113","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T16:30:39Z","timestamp":1770827439000},"page":"e2559113","source":"Crossref","is-referenced-by-count":6,"title":["Angiotensin II\u2013Stimulating Antihypertensive Medications and Dementia-Related Neuropathology"],"prefix":"10.1001","volume":"9","author":[{"given":"Shelly L.","family":"Gray","sequence":"first","affiliation":[{"name":"Department of Pharmacy, School of Pharmacy, University of Washington, Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onchee","family":"Yu","sequence":"additional","affiliation":[{"name":"Kaiser Permanente Washington Health Research Institute, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M.","family":"Gatto","sequence":"additional","affiliation":[{"name":"Kaiser Permanente Washington Health Research Institute, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary A.","family":"Marcum","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Pharmacy, University of Washington, Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin S.","family":"Latimer","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Postupna","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ru","family":"Su","sequence":"additional","affiliation":[{"name":"Kaiser Permanente Washington Health Research Institute, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Barthold","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Pharmacy, University of Washington, Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Willem","family":"van Dalen","sequence":"additional","affiliation":[{"name":"Department of Public and Occupational Health, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands"},{"name":"Department of Neurology, Donders Institute for Brain, Behaviour and Cognition, Radboud University Medical Centre, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edo","family":"Richard","sequence":"additional","affiliation":[{"name":"Department of Public and Occupational Health, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands"},{"name":"Department of Neurology, Donders Institute for Brain, Behaviour and Cognition, Radboud University Medical Centre, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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