{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:04:28Z","timestamp":1780358668296,"version":"3.54.1"},"posted":{"date-parts":[[2024,2,28]]},"group-title":"Neurology","reference-count":53,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,2,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Retrotransposons are viral-like DNA sequences that constitute approximately 41% of the human genome. Studies in\n                  <jats:italic>Drosophila,<\/jats:italic>\n                  mice, cultured cells, and human brain indicate that retrotransposons are activated in settings of tauopathy, including Alzheimer\u2019s disease, and causally drive neurodegeneration. The anti-retroviral medication 3TC (lamivudine), a nucleoside analog reverse transcriptase inhibitor, limits retrotransposon activation and suppresses neurodegeneration in tau transgenic\n                  <jats:italic>Drosophila,<\/jats:italic>\n                  two mouse models of tauopathy, and in brain assembloids derived from patients with sporadic Alzheimer\u2019s disease. We performed a 24-week phase 2a open-label clinical trial of 300 mg daily oral 3TC (\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04552795\">NCT04552795<\/jats:ext-link>\n                  ) in 12 participants aged 52-83 years with a diagnosis of mild cognitive impairment due to suspected Alzheimer\u2019s disease. Primary outcomes included feasibility, blood brain barrier penetration, effects of 3TC on reverse transcriptase activity in the periphery, and safety. Secondary outcomes included changes in cognition and fluid-based biomarkers of neurodegeneration and neuroinflammation. All participants completed the six-month trial; one event of gastrointestinal bleeding due to a peptic ulcer was reported. 3TC was detected in blood and cerebrospinal fluid (CSF) of all participants, suggestive of adherence to study drug and effective brain penetration. Cognitive measures remained stable throughout the study. Glial fibrillary acidic protein (GFAP) (\n                  <jats:italic>P<\/jats:italic>\n                  =0.03) and Flt1 (\n                  <jats:italic>P<\/jats:italic>\n                  =0.05) were significantly reduced in CSF over the treatment period; A\u03b242\/40 (\n                  <jats:italic>P<\/jats:italic>\n                  =0.009) and IL-15 (\n                  <jats:italic>P<\/jats:italic>\n                  =0.006) were significantly elevated in plasma. While this is an open label study of small sample size, the significant decrease of some neurodegeneration- and neuroinflammation-related biomarkers in CSF, significantly elevated levels of plasma A\u03b242\/40, and a trending decrease of CSF NfL after six months of 3TC exposure suggest a beneficial effect on subjects with mild cognitive impairment due to suspected Alzheimer\u2019s disease. Feasibility, safety, tolerability, and central nervous system (CNS) penetration assessments further support clinical evaluation of 3TC in a larger placebo-controlled, multi-dose clinical trial.\n                <\/jats:p>","DOI":"10.1101\/2024.02.26.24303316","type":"posted-content","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T13:50:10Z","timestamp":1709128210000},"source":"Crossref","is-referenced-by-count":10,"title":["A pilot study to investigate the safety and feasibility of antiretroviral therapy for Alzheimer\u2019s disease (ART-AD)"],"prefix":"10.64898","author":[{"given":"A. Campbell","family":"Sullivan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2118-1990","authenticated-orcid":false,"given":"Gabrielle","family":"Zuniga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8532-9590","authenticated-orcid":false,"given":"Paulino","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1670-2838","authenticated-orcid":false,"given":"Chen-Pin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Davila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9066-4366","authenticated-orcid":false,"given":"Kristine","family":"Pelton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1480-2421","authenticated-orcid":false,"given":"Claira","family":"Sohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0285-1012","authenticated-orcid":false,"given":"Marisa","family":"Lopez-Cruzan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6743-8379","authenticated-orcid":false,"given":"Eduardo","family":"Zilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6423-4461","authenticated-orcid":false,"given":"Gabriel A.","family":"de Erausquin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6135-2622","authenticated-orcid":false,"given":"Sudha","family":"Seshadri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1116-302X","authenticated-orcid":false,"given":"Sara","family":"Espinoza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4242-2888","authenticated-orcid":false,"given":"Nicolas","family":"Musi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1212-8138","authenticated-orcid":false,"given":"Bess","family":"Frost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024022923351283000_2024.02.26.24303316v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.07.150"},{"key":"2024022923351283000_2024.02.26.24303316v1.2","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/alz.12694","article-title":"Global estimates on the number of persons across the Alzheimer\u2019s disease continuum","volume":"19","year":"2023","journal-title":"Alzheimers Dement"},{"key":"2024022923351283000_2024.02.26.24303316v1.3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001694"},{"key":"2024022923351283000_2024.02.26.24303316v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-023-00523-w"},{"key":"2024022923351283000_2024.02.26.24303316v1.5","first-page":"E1391","article-title":"Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet","volume":"101","year":"2023","journal-title":"Neurology"},{"key":"2024022923351283000_2024.02.26.24303316v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(97)00056-0"},{"key":"2024022923351283000_2024.02.26.24303316v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0194-1"},{"key":"2024022923351283000_2024.02.26.24303316v1.8","doi-asserted-by":"crossref","unstructured":"Ramirez, P. et al. Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system. Prog Neurobiol 208, 102181 (2022).","DOI":"10.1016\/j.pneurobio.2021.102181"},{"key":"2024022923351283000_2024.02.26.24303316v1.9","doi-asserted-by":"crossref","unstructured":"Ochoa, E. et al. Pathogenic tau-induced transposable element-derived dsRNA drives neuroinflammation. Sci Adv 9, eabq5423 (2023).","DOI":"10.1126\/sciadv.abq5423"},{"key":"2024022923351283000_2024.02.26.24303316v1.10","first-page":"2874","article-title":"Tau Activates Transposable Elements in Alzheimer\u2019s Disease","volume":"23","year":"2018","journal-title":"CellReports"},{"key":"2024022923351283000_2024.02.26.24303316v1.11","doi-asserted-by":"crossref","unstructured":"Vall\u00e9s-Saiz, L. , \u00c1vila, J. & Hern\u00e1ndez, F . Lamivudine (3TC), a Nucleoside Reverse Transcriptase Inhibitor, Prevents the Neuropathological Alterations Present in Mutant Tau Transgenic Mice. Int J Mol Sci 24, (2023).","DOI":"10.1101\/2023.06.02.543424"},{"key":"2024022923351283000_2024.02.26.24303316v1.12","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13798"},{"key":"2024022923351283000_2024.02.26.24303316v1.13","doi-asserted-by":"crossref","unstructured":"Tam, O. H. , Ostrow, L. W. & Gale Hammell, M . Diseases of the nERVous system: Retrotransposon activity in neurodegenerative disease. Mob DNA 10, 32 (2019).","DOI":"10.1186\/s13100-019-0176-1"},{"key":"2024022923351283000_2024.02.26.24303316v1.14","doi-asserted-by":"crossref","unstructured":"J\u00f6nsson, M. E. et al. Activation of endogenous retroviruses during brain development causes an inflammatory response. EMBO J 40, (2021).","DOI":"10.15252\/embj.2020106423"},{"key":"2024022923351283000_2024.02.26.24303316v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.139"},{"key":"2024022923351283000_2024.02.26.24303316v1.16","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41586-018-0784-9","article-title":"L1 drives IFN in senescent cells and promotes age-associated inflammation","volume":"566","year":"2019","journal-title":"Nature"},{"key":"2024022923351283000_2024.02.26.24303316v1.17","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-020-01904-7"},{"key":"2024022923351283000_2024.02.26.24303316v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.02.014"},{"key":"2024022923351283000_2024.02.26.24303316v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2018.02.007"},{"key":"2024022923351283000_2024.02.26.24303316v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.01.089"},{"key":"2024022923351283000_2024.02.26.24303316v1.21","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1007\/s11357-022-00580-w","article-title":"A retrotransposon storm marks clinical phenoconversion to late-onset Alzheimer\u2019s disease","volume":"44","year":"2022","journal-title":"Geroscience"},{"key":"2024022923351283000_2024.02.26.24303316v1.22","first-page":"2874","article-title":"Tau Activates Transposable Elements in Alzheimer\u2019s Disease","volume":"5","year":"2018","journal-title":"Cell Rep"},{"key":"2024022923351283000_2024.02.26.24303316v1.23","doi-asserted-by":"crossref","unstructured":"Ochoa, E. et al. Pathogenic tau-induced transposable element-derived dsRNA drives neuroinflammation. Sci Adv 9, eabq5423 (2023).","DOI":"10.1126\/sciadv.abq5423"},{"key":"2024022923351283000_2024.02.26.24303316v1.24","doi-asserted-by":"publisher","DOI":"10.1101\/2023.05.24.542155"},{"key":"2024022923351283000_2024.02.26.24303316v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-3542(01)00210-8"},{"key":"2024022923351283000_2024.02.26.24303316v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/S1089-3261(03)00023-0"},{"key":"2024022923351283000_2024.02.26.24303316v1.27","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1097\/00002030-199212000-00008","article-title":"The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection: a phase I study","volume":"6","year":"1992","journal-title":"AIDS"},{"key":"2024022923351283000_2024.02.26.24303316v1.28","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0000000000001660"},{"key":"2024022923351283000_2024.02.26.24303316v1.29","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.17.23287375"},{"key":"2024022923351283000_2024.02.26.24303316v1.30","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05599-11"},{"key":"2024022923351283000_2024.02.26.24303316v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-0934(96)02168-4"},{"key":"2024022923351283000_2024.02.26.24303316v1.32","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1111\/j.1572-0241.2002.06063.x","article-title":"Lamivudine-associated thrombocytopenia","volume":"97","year":"2002","journal-title":"Am J Gastroenterol"},{"key":"2024022923351283000_2024.02.26.24303316v1.33","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1111\/j.1572-0241.2001.03806.x","article-title":"Hepatic Decompensation Associated With Lamivudine: A Case Report and Review of Lamivudine-Induced Hepatotoxicity","volume":"96","year":"2001","journal-title":"American Journal of Gastroenterology"},{"key":"2024022923351283000_2024.02.26.24303316v1.34","doi-asserted-by":"crossref","unstructured":"Kakubu, M. A. M. , Bikinesi, T. & Katoto, P. D. M. C . Lamivudine induced pure red cell aplasia and HIV-1 drug resistance-associated mutations: a case report. Oxf Med Case Reports 2023, 106\u2013109 (2023).","DOI":"10.1093\/omcr\/omad022"},{"key":"2024022923351283000_2024.02.26.24303316v1.35","first-page":"1492","article-title":"Weight and Metabolic Changes After Switching From Tenofovir Alafenamide\/Emtricitabine (FTC) +Dolutegravir (DTG), Tenofovir Disoproxil Fumarate (TDF)\/FTC + DTG, and TDF\/FTC\/Efavirenz to TDF\/Lamivudine\/DTG","volume":"76","year":"2022","journal-title":". Clinical Infectious Diseases \u00ae"},{"key":"2024022923351283000_2024.02.26.24303316v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2017.10.004"},{"key":"2024022923351283000_2024.02.26.24303316v1.37","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1002\/alz.12724","article-title":"Plasma A\u03b242\/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer\u2019s disease continuum: A cross-sectional and longitudinal study in the AIBL cohort","volume":"19","year":"2023","journal-title":"Alzheimer\u2019s and Dementia"},{"key":"2024022923351283000_2024.02.26.24303316v1.38","first-page":"e867","article-title":"CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease","volume":"91","year":"2018","journal-title":"Neurology"},{"key":"2024022923351283000_2024.02.26.24303316v1.39","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199936010-00004"},{"key":"2024022923351283000_2024.02.26.24303316v1.40","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008081"},{"key":"2024022923351283000_2024.02.26.24303316v1.41","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jalz.2012.12.006","article-title":"Changes in plasma amyloid beta in a longitudinal study of aging and Alzheimer\u2019s disease","volume":"10","year":"2014","journal-title":"Alzheimer\u2019s and Dementia"},{"key":"2024022923351283000_2024.02.26.24303316v1.42","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25334"},{"key":"2024022923351283000_2024.02.26.24303316v1.43","first-page":"34","article-title":"Plasma A\u03b242\/40 Ratio Detects Early Stages of Alzheimer\u2019s Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255 Study","volume":"6","year":"2019","journal-title":"J Prev Alzheimers Dis"},{"key":"2024022923351283000_2024.02.26.24303316v1.44","doi-asserted-by":"publisher","DOI":"10.1159\/000050753"},{"key":"2024022923351283000_2024.02.26.24303316v1.45","doi-asserted-by":"crossref","first-page":"541","DOI":"10.3233\/JAD-2009-1075","article-title":"Glial Fibrillary Acidic Protein and Protein S-100B: Different Concentration Pattern of Glial Proteins in Cerebrospinal Fluid of Patients with Alzheimer\u2019s Disease and Creutzfeldt-Jakob Disease","volume":"17","year":"2009","journal-title":"Journal of Alzheimer\u2019s Disease"},{"key":"2024022923351283000_2024.02.26.24303316v1.46","doi-asserted-by":"crossref","first-page":"481","DOI":"10.3233\/JAD-180325","article-title":"Glial Fibrillary Acidic Protein in Serum is Increased in Alzheimer\u2019s Disease and Correlates with Cognitive Impairment","volume":"67","year":"2019","journal-title":"Journal of Alzheimer\u2019s Disease"},{"key":"2024022923351283000_2024.02.26.24303316v1.47","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1001\/jamaneurol.2015.3037","article-title":"Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression","volume":"73","year":"2016","journal-title":"JAMA Neurol"},{"key":"2024022923351283000_2024.02.26.24303316v1.48","doi-asserted-by":"crossref","unstructured":"Mattsson, N. et al. Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol 74, 557 (2017).","DOI":"10.1001\/jamaneurol.2016.6117"},{"key":"2024022923351283000_2024.02.26.24303316v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2019.11.019"},{"key":"2024022923351283000_2024.02.26.24303316v1.50","doi-asserted-by":"publisher","DOI":"10.1176\/appi.neuropsych.19.3.318"},{"key":"2024022923351283000_2024.02.26.24303316v1.51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0176760"},{"key":"2024022923351283000_2024.02.26.24303316v1.52","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2019.1632899"},{"key":"2024022923351283000_2024.02.26.24303316v1.53","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1810983"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.02.26.24303316","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:53:28Z","timestamp":1768506808000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.02.26.24303316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,28]]},"references-count":53,"URL":"https:\/\/doi.org\/10.1101\/2024.02.26.24303316","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s44400-024-00001-z","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,2,28]]},"subtype":"preprint"}}