{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:56:22Z","timestamp":1792522582968,"version":"4.5.0"},"reference-count":35,"publisher":"American Medical Association (AMA)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Prevalent use of antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those that do not stimulate these receptors, has been associated with a lower risk of dementia. However, previous studies were limited by inclusion of individuals with prevalent hypertension and a history of antihypertensive use prior to the start of the study, which can introduce bias.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To examine the association of new use of antihypertensive medication regimens that stimulate vs inhibit type 2 and 4 angiotensin II receptors with Alzheimer disease and related dementias (ADRD) among Medicare beneficiaries.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This cohort study was conducted among 57\u202f773 Medicare fee-for-service beneficiaries (January 1, 2006, through December 31, 2018) aged 65 years or older with incident hypertension. Data analysis was conducted from January 1 through June 30, 2022.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n Initiation of antihypertensive medication regimens that stimulate or inhibit type 2 and 4 angiotensin II receptors, or mixed regimens (both stimulating and inhibiting), with the time-dependent measure being each 30-day interval.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was time to first occurrence of ADRD (Centers for Medicare &amp;amp; Medicaid Services Chronic Conditions Data Warehouse definition). Cox proportional hazards regression modeling with time-dependent variables was performed to estimate the association between time-dependent treatment groups and time to ADRD, after adjusting for sociodemographic and clinical characteristics.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n The sample included 57\u202f773 Medicare beneficiaries (36\u202f348 women [62.9%]; mean [SD] age, 73.8 [6.3] years; 2954 [5.1%] Black, 1545 [2.7%] Hispanic; 50\u202f184 [86.9%] White, and 3090 [5.4%] Other individuals [the Other category included individuals of American Indian, Asian, other, or unknown race and ethnicity]). During a median of 6.9 years (IQR, 4.7-9.3 years) of follow-up, the unadjusted incidence density rate of ADRD was 2.2 cases per 100 person-years (95% CI, 2.1-2.4 cases per 100 person-years) for the group receiving regimens that stimulate type 2 and 4 angiotensin II receptors compared with 3.1 cases per 100 person-years (95% CI, 3.0-3.2 cases per 100 person-years) for the group receiving regimens that inhibit type 2 and 4 angiotensin II receptors and 2.7 cases per 100 person-years (95% CI, 2.6-2.9 cases per 100 person-years) for the group receiving mixed treatment regimens. In adjusted Cox proportional hazards regression modeling, stimulating treatment was associated with a statistically significant 16% reduction in the hazard of ADRD compared with inhibiting treatment (hazard ratio, 0.84; 95% CI, 0.79-0.90). Mixed regimen use was also associated with reduced hazards of ADRD compared with the inhibiting group (hazard ratio, 0.90; 95% CI, 0.84-0.96).<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n This cohort study of Medicare beneficiaries suggests that use of antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors was associated with lower risk of ADRD compared with antihypertensive medications that inhibit these receptors. Confirmation is needed in a randomized trial.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2022.49370","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T11:01:08Z","timestamp":1672830068000},"page":"e2249370","source":"Crossref","is-referenced-by-count":34,"title":["Association of New Use of Antihypertensives That Stimulate vs Inhibit Type 2 and 4 Angiotensin II Receptors With Dementia Among Medicare Beneficiaries"],"prefix":"10.1001","volume":"6","author":[{"given":"Zachary A.","family":"Marcum","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Washington School of Pharmacy, Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"Gabriel","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam P.","family":"Bress","sequence":"additional","affiliation":[{"name":"Division of Health System Innovation and Research, Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City"},{"name":"George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah"},{"name":"Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"issue":"10248","key":"zoi221398r1","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S0140-6736(20)30367-6","article-title":"Dementia prevention, intervention, and care: 2020 report of the Lancet Commission.","volume":"396","author":"Livingston","year":"2020","journal-title":"Lancet"},{"issue":"3","key":"zoi221398r3","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.3233\/JAD-171119","article-title":"The coming of age of the angiotensin hypothesis in Alzheimer\u2019s disease: progress toward disease prevention and treatment?","volume":"62","author":"Kehoe","year":"2018","journal-title":"J Alzheimers Dis"},{"issue":"6","key":"zoi221398r4","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1097\/HJH.0b013e3283603f53","article-title":"Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis.","volume":"31","author":"Levi Marpillat","year":"2013","journal-title":"J Hypertens"},{"issue":"7","key":"zoi221398r5","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1016\/j.jamda.2020.12.019","article-title":"Antihypertensive medication classes and the risk of dementia: a systematic review and network meta-analysis.","volume":"22","author":"den Brok","year":"2021","journal-title":"J Am Med Dir Assoc"},{"issue":"8","key":"zoi221398r6","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.12252","article-title":"Effects of candesartan vs lisinopril on neurocognitive function in older adults with executive mild cognitive impairment: a randomized clinical trial.","volume":"3","author":"Hajjar","year":"2020","journal-title":"JAMA Netw Open"},{"issue":"1","key":"zoi221398r8","doi-asserted-by":"publisher","first-page":"e67","DOI":"10.1212\/WNL.0000000000010996","article-title":"Association of angiotensin II\u2013stimulating antihypertensive use and dementia risk: post hoc analysis of the PreDIVA trial.","volume":"96","author":"van Dalen","year":"2021","journal-title":"Neurology"},{"issue":"1","key":"zoi221398r9","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.45319","article-title":"Association of antihypertensives that stimulate vs inhibit types 2 and 4 angiotensin II receptors with cognitive impairment.","volume":"5","author":"Marcum","year":"2022","journal-title":"JAMA Netw Open"},{"issue":"2","key":"zoi221398r10","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s40256-019-00371-3","article-title":"Adherence to anticoagulation and risk of stroke among Medicare beneficiaries newly diagnosed with atrial fibrillation.","volume":"20","author":"Hernandez","year":"2020","journal-title":"Am J Cardiovasc Drugs"},{"issue":"4","key":"zoi221398r12","doi-asserted-by":"publisher","first-page":"807","DOI":"10.3233\/JAD-2009-1099","article-title":"The accuracy of Medicare claims as an epidemiological tool: the case of dementia revisited.","volume":"17","author":"Taylor","year":"2009","journal-title":"J Alzheimers Dis"},{"issue":"9","key":"zoi221398r13","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/S0895-4356(02)00452-3","article-title":"The accuracy of Medicare claims data in identifying Alzheimer\u2019s disease.","volume":"55","author":"Taylor","year":"2002","journal-title":"J Clin Epidemiol"},{"issue":"2","key":"zoi221398r14","doi-asserted-by":"publisher","first-page":"769","DOI":"10.3233\/JAD-181005","article-title":"Evaluation of Medicare claims data as a tool to identify dementia.","volume":"67","author":"Lee","year":"2019","journal-title":"J Alzheimers Dis"},{"key":"zoi221398r16","doi-asserted-by":"publisher","DOI":"10.31478\/namperspectives","article-title":"Can preferentially prescribing angiotensin II receptor blockers (ARBs) over angiotensin-converting enzyme inhibitors (ACEIs) decrease dementia risk and improve brain health equity?","author":"Marcum","journal-title":"NAM Perspect"},{"issue":"3","key":"zoi221398r17","first-page":"329","article-title":"Cerebroprotective effect of angiotensin IV in experimental ischemic stroke in the rat mediated by AT4 receptors.","volume":"57","author":"Faure","year":"2006","journal-title":"J Physiol Pharmacol"},{"issue":"4","key":"zoi221398r18","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/j.neuropharm.2006.05.029","article-title":"Comparison of inhibitory action of candesartan and enalapril on brain ischemia through inhibition of oxidative stress.","volume":"51","author":"Hamai","year":"2006","journal-title":"Neuropharmacology"},{"issue":"1","key":"zoi221398r19","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1291\/hypres.31.161","article-title":"Attenuation of focal brain ischemia by telmisartan, an angiotensin II type 1 receptor blocker, in atherosclerotic apolipoprotein E\u2013deficient mice.","volume":"31","author":"Iwai","year":"2008","journal-title":"Hypertens Res"},{"issue":"7","key":"zoi221398r20","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1161\/01.CIR.0000138848.58269.80","article-title":"Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor stimulation.","volume":"110","author":"Iwai","year":"2004","journal-title":"Circulation"},{"issue":"2","key":"zoi221398r21","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.neuroscience.2003.12.006","article-title":"Effect of I.C.V. injection of AT4 receptor ligands, NLE1-angiotensin IV and LVV-hemorphin 7, on spatial learning in rats.","volume":"124","author":"Lee","year":"2004","journal-title":"Neuroscience"},{"issue":"6","key":"zoi221398r22","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1096\/fsb2.v19.6","article-title":"Angiotensin AT2 receptor protects against cerebral ischemia\u2013induced neuronal injury.","volume":"19","author":"Li","year":"2005","journal-title":"FASEB J"},{"issue":"17","key":"zoi221398r23","doi-asserted-by":"publisher","first-page":"1963","DOI":"10.1097\/01.wnr.0000187636.13147.cd","article-title":"Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats.","volume":"16","author":"Lu","year":"2005","journal-title":"Neuroreport"},{"issue":"11","key":"zoi221398r24","doi-asserted-by":"publisher","first-page":"3393","DOI":"10.1172\/JCI31547","article-title":"Valsartan lowers brain \u00df-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease.","volume":"117","author":"Wang","year":"2007","journal-title":"J Clin Invest"},{"issue":"8","key":"zoi221398r25","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1097\/HJH.0b013e32814a5ae5","article-title":"Does a change in angiotensin II formation caused by antihypertensive drugs affect the risk of stroke? a meta-analysis of trials according to treatment with potentially different effects on angiotensin II.","volume":"25","author":"Boutitie","year":"2007","journal-title":"J Hypertens"},{"issue":"4","key":"zoi221398r26","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1592\/phco.25.4.531.61022","article-title":"Can the renin-angiotensin system protect against stroke? a focus on angiotensin II receptor blockers.","volume":"25","author":"Epstein","year":"2005","journal-title":"Pharmacotherapy"},{"issue":"12","key":"zoi221398r27","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1001\/archneurol.2012.1010","article-title":"Impact of angiotensin receptor blockers on Alzheimer disease neuropathology in a large brain autopsy series.","volume":"69","author":"Hajjar","year":"2012","journal-title":"Arch Neurol"},{"issue":"9","key":"zoi221398r28","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1001\/jamaneurol.2015.1001","article-title":"Association between angiotensin receptor blockers and longitudinal decline in tau in mild cognitive impairment.","volume":"72","author":"Hajjar","year":"2015","journal-title":"JAMA Neurol"},{"issue":"7-8","key":"zoi221398r29","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1007\/s10571-006-9009-0","article-title":"Mechanisms of the anti-ischemic effect of angiotensin II AT1 receptor antagonists in the brain.","volume":"26","author":"Saavedra","year":"2006","journal-title":"Cell Mol Neurobiol"},{"issue":"3","key":"zoi221398r30","doi-asserted-by":"publisher","first-page":"168","DOI":"10.3317\/jraas.2006.027","article-title":"Cognitive effects attributed to angiotensin II may result from its conversion to angiotensin IV.","volume":"7","author":"Braszko","year":"2006","journal-title":"J Renin Angiotensin Aldosterone Syst"},{"issue":"3-4","key":"zoi221398r31","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/S0891-0618(00)00112-5","article-title":"Distribution of angiotensin IV binding sites (AT4 receptor) in the human forebrain, midbrain and pons as visualised by in vitro receptor autoradiography.","volume":"20","author":"Chai","year":"2000","journal-title":"J Chem Neuroanat"},{"issue":"2-3","key":"zoi221398r32","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/S0167-0115(98)00028-7","article-title":"Attenuation of scopolamine-induced spatial learning impairments by an angiotensin IV analog.","volume":"74","author":"Pederson","year":"1998","journal-title":"Regul Pept"},{"issue":"2-3","key":"zoi221398r33","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/S0167-0115(01)00312-3","article-title":"A role for the angiotensin AT4 receptor subtype in overcoming scopolamine-induced spatial memory deficits.","volume":"102","author":"Pederson","year":"2001","journal-title":"Regul Pept"},{"issue":"10","key":"zoi221398r34","doi-asserted-by":"publisher","first-page":"3952","DOI":"10.1523\/JNEUROSCI.19-10-03952.1999","article-title":"Contributions of the brain angiotensin IV-AT4 receptor subtype system to spatial learning.","volume":"19","author":"Wright","year":"1999","journal-title":"J Neurosci"},{"issue":"1","key":"zoi221398r35","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1111\/jgs.v68.1","article-title":"Development and validation of the Electronic Health Record Risk of Alzheimer\u2019s and Dementia Assessment Rule (eRADAR).","volume":"68","author":"Barnes","year":"2020","journal-title":"J Am Geriatr Soc"},{"key":"zoi221398r2","year":"2017"},{"key":"zoi221398r7","unstructured":"ClinicalTrials.gov. Risk Reduction for Alzheimer\u2019s Disease (rrAD). ClinicalTrials.gov identifier: NCT02913664. Accessed June 19, 2022. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02913664"},{"key":"zoi221398r11","unstructured":"Chronic Conditions Data Warehouse. Data dictionaries. Accessed June 19, 2022. https:\/\/www2.ccwdata.org\/web\/guest\/data-dictionaries"},{"key":"zoi221398r15","unstructured":"Aging Brain Program, Indiana University Center for Aging Research. Anticholinergic Cognitive Burden Scale: 2012 update. Accessed June 19, 2022. http:\/\/www.idhca.org\/wp-content\/uploads\/2018\/02\/DESAI_ACB_scale_-_Legal_size_paper.pdf"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2800004\/marcum_2023_oi_221398_1671470068.0929.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T11:01:21Z","timestamp":1672830081000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2800004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,4]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1,3]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2022.49370","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,4]]}}}