{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:30:47Z","timestamp":1793723447156,"version":"4.6.1"},"posted":{"date-parts":[[2025,8,12]]},"group-title":"Neurology","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T00:00:00Z","timestamp":1754956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Reportedly, over 60% of individuals in the USA aged 65 or older take antihypertensive medications, making it crucial to evaluate their potential impact on dementia. Alzheimer\u2019s disease (AD), the most prevalent form of dementia, develops insidiously over decades, effectively precluding clinical trials of antihypertensive drug effects on AD risk. Through a triangulation approach integrating large-scale human genetics, population-based study, and rigorous experimental models, we identified that angiotensin-converting enzyme (ACE) inhibitors were associated with increased AD risk, with no significant associations observed for other antihypertensive classes, including angiotensin II receptor blockers and calcium channel blockers. Multi-omics Mendelian randomization analyses revealed that genetically proxied reductions in\n                  <jats:italic>ACE<\/jats:italic>\n                  expression and ACE protein levels in serum, cerebrospinal fluid, and brain tissues were causally associated with increased AD risk via exacerbated tau phosphorylation. A cohort study of 338,645 UK Biobank participants, followed for more than 10 years, also found an association between genetically predicted low serum ACE levels and the increased incidence of AD. Experimental validation using P301S tau transgenic mice and human iPSC-derived neurons confirmed that pharmacological ACE inhibition intensified tau phosphorylation and aggregation, cognitive impairment, neuroinflammation, and glial activation, predominantly in the hippocampal region. Multiple lines of evidence established a specific link between ACE inhibition and tau-driven neurodegeneration, underscoring the importance of carefully tailored antihypertensive strategies to prevent dementia risk, and identifying ACE as a viable therapeutic target for AD and other tau-related neurodegenerative conditions.\n                <\/jats:p>","DOI":"10.1101\/2025.08.11.25333412","type":"posted-content","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T01:45:19Z","timestamp":1755049519000},"source":"Crossref","is-referenced-by-count":6,"title":["ACE inhibition increases Alzheimer\u2019s disease risk by promoting tau phosphorylation"],"prefix":"10.64898","author":[{"given":"Min Seo","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunyoung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Ho","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woojae","family":"Myung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minku","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron","family":"Do","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangsik","family":"Nho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunae","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seonghoon","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep","family":"Natarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Jin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo Jin","family":"Son","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woong-Yang","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Sui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akl C","family":"Fahed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick T.","family":"Ellinor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Keon","family":"Yon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsoo","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Young","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Gyu","family":"Jo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Hee","family":"Won","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025081405400807000_2025.08.11.25333412v1.1","doi-asserted-by":"crossref","first-page":"533","DOI":"10.15585\/mmwr.mm6918a1","article-title":"Prevalence of Self-Reported Hypertension and Antihypertensive Medication Use by County and Rural-Urban Classification - United States, 2017","volume":"69","year":"2020","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"2025081405400807000_2025.08.11.25333412v1.2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.4249"},{"key":"2025081405400807000_2025.08.11.25333412v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0020-3"},{"key":"2025081405400807000_2025.08.11.25333412v1.4","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1093\/eurheartj\/ehy407","article-title":"Association is not causation: treatment effects cannot be estimated from observational data in heart failure","volume":"39","year":"2018","journal-title":"Eur Heart J"},{"key":"2025081405400807000_2025.08.11.25333412v1.5","doi-asserted-by":"crossref","unstructured":"M. S. Kim , M. Song , J. I. Shin , H.-H. Won , How to interpret studies using Mendelian randomisation. BMJ Evidence-Based Medicine, (2023).","DOI":"10.1136\/bmjebm-2022-112149"},{"key":"2025081405400807000_2025.08.11.25333412v1.6","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyg070"},{"key":"2025081405400807000_2025.08.11.25333412v1.7","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k601"},{"key":"2025081405400807000_2025.08.11.25333412v1.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1806747"},{"key":"2025081405400807000_2025.08.11.25333412v1.9","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.0150"},{"key":"2025081405400807000_2025.08.11.25333412v1.10","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1001\/jamapsychiatry.2021.0005","article-title":"Association of Antihypertensive Drug Target Genes With Psychiatric Disorders: A Mendelian Randomization Study","volume":"78","year":"2021","journal-title":"JAMA Psychiatry"},{"key":"2025081405400807000_2025.08.11.25333412v1.11","doi-asserted-by":"crossref","first-page":"e1003898","DOI":"10.1371\/journal.pmed.1003898","article-title":"The evolution of mendelian randomization for investigating drug effects","volume":"19","year":"2022","journal-title":"PLoS Med"},{"key":"2025081405400807000_2025.08.11.25333412v1.12","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1309-z"},{"key":"2025081405400807000_2025.08.11.25333412v1.13","doi-asserted-by":"crossref","unstructured":"S. H. Lee , E. J. Bae , S. J. Park , S. J. Lee , Microglia-driven inflammation induces progressive tauopathies and synucleinopathies. Exp Mol Med, (2025).","DOI":"10.1038\/s12276-025-01450-z"},{"key":"2025081405400807000_2025.08.11.25333412v1.14","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41467-020-20322-w","article-title":"Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex","volume":"12","year":"2021","journal-title":"Nat Commun"},{"key":"2025081405400807000_2025.08.11.25333412v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-023-05788-0"},{"key":"2025081405400807000_2025.08.11.25333412v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01315-6"},{"key":"2025081405400807000_2025.08.11.25333412v1.17","doi-asserted-by":"crossref","unstructured":"A. R. Gomez et al., Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer\u2019s disease in 5xFAD mice. Nature Aging, 1\u201315 (2025).","DOI":"10.1038\/s43587-025-00879-1"},{"key":"2025081405400807000_2025.08.11.25333412v1.18","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222413178"},{"key":"2025081405400807000_2025.08.11.25333412v1.19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66541"},{"key":"2025081405400807000_2025.08.11.25333412v1.20","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt257"},{"key":"2025081405400807000_2025.08.11.25333412v1.21","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz364"},{"key":"2025081405400807000_2025.08.11.25333412v1.22","doi-asserted-by":"crossref","first-page":"115756","DOI":"10.1016\/j.biopha.2023.115756","article-title":"Angiotensin-converting enzyme inhibitors and statins therapies-induced changes in omics profiles in humans and transgenic tau mice","volume":"168","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"2025081405400807000_2025.08.11.25333412v1.23","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2021-057510"},{"key":"2025081405400807000_2025.08.11.25333412v1.24","doi-asserted-by":"crossref","first-page":"e066498","DOI":"10.1002\/alz.066498","article-title":"Association between centrally active angiotensin-converting enzyme inhibitors with dementia risk","volume":"19","year":"2023","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2025081405400807000_2025.08.11.25333412v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03911-7"},{"key":"2025081405400807000_2025.08.11.25333412v1.26","doi-asserted-by":"crossref","unstructured":"S. Burgess et al., Guidelines for performing Mendelian randomization investigations. Wellcome Open Res 4, 186 (2019).","DOI":"10.12688\/wellcomeopenres.15555.1"},{"key":"2025081405400807000_2025.08.11.25333412v1.27","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k601"},{"key":"2025081405400807000_2025.08.11.25333412v1.28","doi-asserted-by":"publisher","DOI":"10.1001\/JAMA.2021.18236"},{"key":"2025081405400807000_2025.08.11.25333412v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00776-w"},{"key":"2025081405400807000_2025.08.11.25333412v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0358-2"},{"key":"2025081405400807000_2025.08.11.25333412v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-018-0311-9"},{"key":"2025081405400807000_2025.08.11.25333412v1.32","doi-asserted-by":"publisher","DOI":"10.1177\/0022146515594631.Marriage"},{"key":"2025081405400807000_2025.08.11.25333412v1.33","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz1776"},{"key":"2025081405400807000_2025.08.11.25333412v1.34","first-page":"526","article-title":"Evaluating the Potential Benefits and Pitfalls of Combining Protein and Expression Quantitative Trait Loci in Evidencing Drug Targets","volume":"46","year":"2022","journal-title":"Genet Epidemiol"},{"key":"2025081405400807000_2025.08.11.25333412v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00978-w"},{"key":"2025081405400807000_2025.08.11.25333412v1.36","doi-asserted-by":"crossref","unstructured":"J. Zhang , et al., Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies. bioRxiv, 2021.2003.2015.435533 (2022).","DOI":"10.1101\/2021.03.15.435533"},{"key":"2025081405400807000_2025.08.11.25333412v1.37","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1074"},{"key":"2025081405400807000_2025.08.11.25333412v1.38","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkj067"},{"key":"2025081405400807000_2025.08.11.25333412v1.39","doi-asserted-by":"publisher","DOI":"10.1093\/IJE\/DYW220"},{"key":"2025081405400807000_2025.08.11.25333412v1.40","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyr036"},{"key":"2025081405400807000_2025.08.11.25333412v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0099-7"},{"key":"2025081405400807000_2025.08.11.25333412v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3538"},{"key":"2025081405400807000_2025.08.11.25333412v1.43","doi-asserted-by":"publisher","DOI":"10.1093\/HMG\/DDY163"},{"key":"2025081405400807000_2025.08.11.25333412v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0205-x"},{"key":"2025081405400807000_2025.08.11.25333412v1.45","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.9879"},{"key":"2025081405400807000_2025.08.11.25333412v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09718-5"},{"key":"2025081405400807000_2025.08.11.25333412v1.47","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac049"},{"key":"2025081405400807000_2025.08.11.25333412v1.48","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1001\/jamapsychiatry.2021.2959","article-title":"Use of the PsycheMERGE Network to Investigate the Association Between Depression Polygenic Scores and White Blood Cell Count","volume":"78","year":"2021","journal-title":"JAMA Psychiatry"},{"key":"2025081405400807000_2025.08.11.25333412v1.49","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jagp.2012.08.017","article-title":"Angiotensin converting enzyme inhibitors and Alzheimer disease in the presence of the apolipoprotein E4 allele","volume":"22","year":"2014","journal-title":"Am J Geriatr Psychiatry"},{"key":"2025081405400807000_2025.08.11.25333412v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3475"},{"key":"2025081405400807000_2025.08.11.25333412v1.51","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyu005"},{"key":"2025081405400807000_2025.08.11.25333412v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2011.12.009"},{"key":"2025081405400807000_2025.08.11.25333412v1.53","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2007.137851"},{"key":"2025081405400807000_2025.08.11.25333412v1.54","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/ana.25645","article-title":"Midlife Atherosclerosis and Development of Alzheimer or Vascular Dementia","volume":"87","year":"2020","journal-title":"Ann Neurol"},{"key":"2025081405400807000_2025.08.11.25333412v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.023"},{"key":"2025081405400807000_2025.08.11.25333412v1.56","doi-asserted-by":"crossref","unstructured":"M. Frega et al., Rapid Neuronal Differentiation of Induced Pluripotent Stem Cells for Measuring Network Activity on Micro-electrode Arrays. J Vis Exp, (2017).","DOI":"10.3791\/54900"},{"key":"2025081405400807000_2025.08.11.25333412v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.06.005"},{"key":"2025081405400807000_2025.08.11.25333412v1.58","doi-asserted-by":"crossref","unstructured":"J. Park et al., O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer\u2019s disease by inhibiting necroptosis. Sci Adv 7, (2021).","DOI":"10.1126\/sciadv.abd3207"},{"key":"2025081405400807000_2025.08.11.25333412v1.59","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1038\/s41380-022-01877-0","article-title":"Cyclin Y regulates spatial learning and memory flexibility through distinct control of the actin pathway","volume":"28","year":"2023","journal-title":"Mol Psychiatry"},{"key":"2025081405400807000_2025.08.11.25333412v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.155"},{"key":"2025081405400807000_2025.08.11.25333412v1.61","doi-asserted-by":"crossref","first-page":"eadi4830","DOI":"10.1126\/scitranslmed.adi4830","article-title":"Engineered exosomes with a photoinducible protein delivery system enable CRISPR-Cas-based epigenome editing in Alzheimer\u2019s disease","volume":"16","year":"2024","journal-title":"Sci Transl Med"},{"key":"2025081405400807000_2025.08.11.25333412v1.62","doi-asserted-by":"crossref","first-page":"e12179","DOI":"10.1002\/jev2.12179","article-title":"Engineered small extracellular vesicles displaying ACE2 variants on the surface protect against SARS-CoV-2 infection","volume":"11","year":"2022","journal-title":"J Extracell Vesicles"},{"key":"2025081405400807000_2025.08.11.25333412v1.63","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2025081405400807000_2025.08.11.25333412v1.64","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-323"},{"key":"2025081405400807000_2025.08.11.25333412v1.65","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2010-11-10-r106"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.08.11.25333412","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:43:04Z","timestamp":1768509784000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.08.11.25333412"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,12]]},"references-count":65,"URL":"https:\/\/doi.org\/10.1101\/2025.08.11.25333412","relation":{},"subject":[],"published":{"date-parts":[[2025,8,12]]},"subtype":"preprint"}}