{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:29:18Z","timestamp":1791919758921,"version":"4.3.4"},"reference-count":58,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer\u2019s disease and related dementias (ADRD), but two recent cohort studies have offered opposing conclusions.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We performed an unmatched case-control study using electronic medical records from a large healthcare system to evaluate the association of PDE5i use and ADRD in patients \u226565 years old.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Odds of PDE5i exposure were 64.2%, 55.7%, and 54.0% lower in patients with ADRD than controls among populations with erectile dysfunction, benign prostatic hyperplasia, and pulmonary hypertension, respectively. We observed odds ratios less than unity among males and females and with exposure to the PDE5i sildenafil (Viagra\u00ae) and tadalafil (Cialis\u00ae). We also evaluated the odds of exposure to two other common treatments for pulmonary hypertension: endothelin receptor antagonists (ERA) and calcium channel blockers (CCB). The odds of ERA exposure were 63.2% lower, but the odds of CCB exposure were 30.7% higher, in patients with ADRD than controls among the population with pulmonary hypertension.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Our results reconcile the opposing conclusions from the previous observational studies and support further research into using PDE5i for prevention and treatment of ADRD.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0292863","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T17:31:11Z","timestamp":1697650271000},"page":"e0292863","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["A\u00a0case-control study of phosphodiesterase-5 inhibitor use and Alzheimer\u2019s disease and related dementias among male and female patients aged 65 years and older supporting the need for a phase III clinical trial"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8237-9303","authenticated-orcid":true,"given":"David S.","family":"Henry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9894-3114","authenticated-orcid":true,"given":"Richard G.","family":"Pellegrino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,10,18]]},"reference":[{"key":"pone.0292863.ref001","volume-title":"StatPearls: Alzheimer Disease.","author":"A Kumar","year":"2022"},{"key":"pone.0292863.ref002","volume-title":"BLA 761178 Approval letter","author":"B. 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Reardon","year":"2023","journal-title":"Nature News"},{"issue":"1","key":"pone.0292863.ref010","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in Early Alzheimer\u2019s Disease","volume":"388","author":"CH van Dyck","year":"2023","journal-title":"N Engl J Med"},{"issue":"12","key":"pone.0292863.ref011","first-page":"1437","article-title":"Aducanumab: First Approval","volume":"81","author":"S. Dhillon","year":"2021","journal-title":"Aug"},{"key":"pone.0292863.ref012","article-title":"Aducanumab for Alzheimer\u2019s disease","author":"S Walsh","year":"2021","journal-title":"BMJ"},{"issue":"4","key":"pone.0292863.ref013","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/alz.12213","article-title":"Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019","volume":"17","author":"DS Knopman","year":"2021","journal-title":"Alzheimers Dement [Internet]"},{"key":"pone.0292863.ref014","author":"T. Buracchio","year":"2023"},{"issue":"8","key":"pone.0292863.ref015","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1001\/archneur.65.8.1091","article-title":"Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer\u2019s research consortium study","volume":"65","author":"SE O\u2019Bryant","year":"2008","journal-title":"Arch Neurol"},{"issue":"2","key":"pone.0292863.ref016","doi-asserted-by":"crossref","first-page":"497","DOI":"10.3233\/JAD-230099","article-title":"The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes","volume":"94","author":"KP Kepp","year":"2023","journal-title":"J Alzheimers Dis"},{"key":"pone.0292863.ref017","article-title":"U.S. Food and Drug Administration Issues Complete Response Letter for Accelerated Approval of Donanemab","author":"Eli Lilly and Company","year":"2023"},{"issue":"6","key":"pone.0292863.ref018","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1001\/jama.2023.13239","article-title":"Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial.","volume":"330","author":"JR Sims","year":"2023","journal-title":"JAMA"},{"issue":"12","key":"pone.0292863.ref019","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1021\/acschemneuro.0c00244","article-title":"Therapeutic Potential of Phosphodiesterase Inhibitors against Neurodegeneration: The Perspective of the Medicinal Chemist.","volume":"11","author":"G Ribaudo","year":"2020","journal-title":"ACS Chem Neurosci"},{"key":"pone.0292863.ref020","article-title":"Therapeutic drug repositioning with special emphasis on neurodegenerative diseases: Threats and issues.","author":"BB Kakoti","year":"2022","journal-title":"Front Pharmacol [Internet]."},{"key":"pone.0292863.ref021","volume-title":"StatPearls: PDE5 Inhibitors. 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mice","volume":"10","author":"CM Baratti","year":"1999","journal-title":"Behavioural pharmacology [Internet]."},{"issue":"1","key":"pone.0292863.ref027","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3233\/NRE-131022","article-title":"Phosphodiesterase inhibition facilitates cognitive restoration in rodent models of age-related memory decline.","volume":"34","author":"BD Devan","year":"2014","journal-title":"NeuroRehabilitation [Internet]"},{"issue":"4","key":"pone.0292863.ref028","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s00213-004-1967-7","article-title":"Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation","volume":"177","author":"J Prickaerts","year":"2005","journal-title":"Psychopharmacology (Berl) 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[Internet]."},{"issue":"12","key":"pone.0292863.ref042","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/s43587-021-00138-z","article-title":"Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer\u2019s disease.","volume":"1","author":"J Fang","year":"2021","journal-title":"Nat Aging [Internet]."},{"issue":"5","key":"pone.0292863.ref043","article-title":"No association between initiation of phosphodiesterase-5 inhibitors and risk of incident Alzheimer\u2019s disease and related dementia: results from the Drug Repurposing for Effective Alzheimer\u2019s Medicines study","volume":"4","author":"RJ Desai","year":"2022","journal-title":"Brain Commun [Internet]."},{"key":"pone.0292863.ref044","author":"Tadalafil","year":"2023","journal-title":"Lexicomp Online"},{"key":"pone.0292863.ref045","author":"Sildenafil","year":"2023","journal-title":"Lexicomp 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function","volume":"33","author":"U F\u00f6rstermann","year":"2012","journal-title":"Eur Heart J [Internet"},{"issue":"4","key":"pone.0292863.ref049","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.nlm.2012.02.008","article-title":"Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: indications for central and peripheral mechanisms","volume":"97","author":"OAH Reneerkens","year":"2012","journal-title":"Neurobiol Learn Mem."},{"issue":"4","key":"pone.0292863.ref050","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1097\/00008571-199508000-00002","article-title":"Evidence for the polymorphic oxidation of debrisoquine and proguanil in a New Zealand Maori population","volume":"5","author":"S Wanwimolruk","year":"1995","journal-title":"Pharmacogenetics"},{"issue":"3","key":"pone.0292863.ref051","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1124\/jpet.108.142976","article-title":"Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist","volume":"327","author":"M Iglarz","year":"2008","journal-title":"J Pharmacol Exp Ther [Internet]."},{"key":"pone.0292863.ref052","doi-asserted-by":"crossref","first-page":"S117","DOI":"10.1016\/0165-1838(94)90098-1","article-title":"Endothelin-A receptors mediate contraction in human cerebral, meningeal and temporal arteries.","volume":"49","author":"M Adner","year":"1994","journal-title":"J Auton Nerv Syst [Internet]"},{"issue":"2","key":"pone.0292863.ref053","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1254\/jphs.13R02CR","article-title":"Endothelin receptor signaling: new insight into its regulatory mechanisms.","volume":"123","author":"T Horinouchi","year":"2013","journal-title":"J Pharmacol Sci [Internet]."},{"issue":"2","key":"pone.0292863.ref054","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1097\/00006123-199702000-00023","article-title":"Presence of contractile endothelin-A and dilatory endothelin-B receptors in human cerebral arteries.","volume":"40","author":"T Nilsson","year":"1997","journal-title":"Neurosurgery [Internet]"},{"key":"pone.0292863.ref055","article-title":"Targeting Endothelin in Alzheimer\u2019s Disease: A Promising Therapeutic Approach","author":"S Sharma","year":"2021","journal-title":"Biomed Res Int [Internet]."},{"issue":"12","key":"pone.0292863.ref056","article-title":"Tadalafil Alone or in Combination with Tamsulosin for the Management for LUTS\/BPH and ED.","volume":"21","author":"A Sebastianelli","year":"2020","journal-title":"Curr Urol Rep [Internet]"},{"issue":"2","key":"pone.0292863.ref057","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1111\/j.1742-1241.2009.02254.x","article-title":"Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database.","volume":"64","author":"F Giuliano","year":"2010","journal-title":"Int J Clin Pract 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