{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:29Z","timestamp":1787028569727,"version":"build-2736575974"},"reference-count":55,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Damaging mutations of the Angiotensin I-converting enzyme (ACE) that result in low ACE levels may increase the risk of developing late-onset Alzheimer\u2019s disease (AD). We quantified blood ACE levels in EDTA-plasma from 147 subjects with 23 different heterozygous ACE mutations (and 70 controls) and estimated the effect of these mutations on ACE phenotype, using a set of monoclonal antibodies (mAbs) to ACE and two ACE substrates. We identified several mutations in both ACE domains (including the most frequent ACE mutation, Y215C), which led to decreased ACE levels in the blood, and thus could be considered as putative risk factors for late-onset AD. The precipitation of several ACE mutants (Q259R, A725P, C734Y) by specific mAbs changed significantly, and therefore, these mAbs could be markers of these mutations. Analysis of 50 of the most frequent ACE mutations demonstrates that more than 1.5% of the adult population may have mutations which lead to decreased ACE levels, and thus, the role of low ACE levels in the development of AD may be underappreciated. Intriguingly, statistical and cluster analyses of longevity patients revealed trends towards higher frequency of cognitive impairment among affected individuals with damaging ACE mutations. Systematic analysis of blood ACE levels in patients with various ACE mutations identifies individuals with low blood ACE levels who may be at increased risk for late-onset AD. Patients with transport-deficient ACE mutations theoretically could benefit from therapeutic treatment with a combination of chemical and pharmacological chaperones and proteasome inhibitors, as was demonstrated previously on a cell model of the transport-deficient ACE mutation Q1069R. Moreover, clinical association analysis suggests a trend linking damaging ACE mutations with increased risk of cognitive impairment.<\/jats:p>","DOI":"10.3390\/ijms26189099","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T12:54:26Z","timestamp":1758200066000},"page":"9099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["ACE-Dependent Alzheimer\u2019s Disease: Circulating ACE Phenotypes in Heterozygous Carriers of Rare ACE Variants"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4108-1214","authenticated-orcid":false,"given":"Iaroslav V.","family":"Mironenko","sequence":"first","affiliation":[{"name":"Institute on Aging Research, Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 129226 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1051-1642","authenticated-orcid":false,"given":"Olga V.","family":"Kryukova","sequence":"additional","affiliation":[{"name":"Chemistry Faculty, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7894-9222","authenticated-orcid":false,"given":"Anastasiia A.","family":"Buianova","sequence":"additional","affiliation":[{"name":"Genomics Laboratory, Pirogov Russian National Research Medical University, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3920-7581","authenticated-orcid":false,"given":"Alexey V.","family":"Churov","sequence":"additional","affiliation":[{"name":"Institute on Aging Research, Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 129226 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail S.","family":"Arbatsky","sequence":"additional","affiliation":[{"name":"Institute on Aging Research, Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 129226 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyona A.","family":"Kubrikova","sequence":"additional","affiliation":[{"name":"Institute on Aging Research, Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 129226 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8318-5241","authenticated-orcid":false,"given":"Yunna S.","family":"Petrusenko","sequence":"additional","affiliation":[{"name":"Biotech Campus LLC, 117437 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4228-6114","authenticated-orcid":false,"given":"Zhanna A.","family":"Repinskaia","sequence":"additional","affiliation":[{"name":"Genomics Laboratory, Pirogov Russian National Research Medical University, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5256-0892","authenticated-orcid":false,"given":"Anna O.","family":"Shmitko","sequence":"additional","affiliation":[{"name":"Genomics Laboratory, Pirogov Russian National Research Medical University, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galit A.","family":"Ilyina","sequence":"additional","affiliation":[{"name":"Genomics Laboratory, Pirogov Russian National Research Medical University, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9665-0523","authenticated-orcid":false,"given":"Olga A.","family":"Kost","sequence":"additional","affiliation":[{"name":"Chemistry Faculty, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5624-0714","authenticated-orcid":false,"given":"Steven M.","family":"Dudek","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina D.","family":"Strazhesko","sequence":"additional","affiliation":[{"name":"Institute on Aging Research, Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 129226 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruslan I.","family":"Isaev","sequence":"additional","affiliation":[{"name":"Institute on Aging Research, Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 129226 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elen A.","family":"Mkhitaryan","sequence":"additional","affiliation":[{"name":"Institute on Aging Research, Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 129226 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga N.","family":"Tkacheva","sequence":"additional","affiliation":[{"name":"Institute on Aging Research, Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 129226 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-1807","authenticated-orcid":false,"given":"Denis V.","family":"Rebrikov","sequence":"additional","affiliation":[{"name":"Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6901-4545","authenticated-orcid":false,"given":"Sergei M.","family":"Danilov","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1471-4159.2011.07575.x","article-title":"Twenty years of Alzheimer\u2019s disease-causing mutations","volume":"129","author":"Goate","year":"2012","journal-title":"J. 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