Repurposing a Combination Antiretroviral Drug Therapy to Target Retrotransposons and Treat Early Alzheimer's Disease

Summary

The goal of this clinical trial is to determine the safety, tolerability, drug levels and biological effects of two doses of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) combination administered daily for 4 weeks in older adults with early Alzheimer's disease. The main questions it aims to answer are: * Is FTC-TDF combination safe in older adults who have early Alzheimer's disease. * To measure the FTC-TDF levels at different times. * To measure the biological effects of FTC-TDF combination. * To measure the effects of FTC-TDF combination on inflammation. Researchers will compare two doses of FTC-TDF combination to a placebo (a look-alike substance that contains no drug) to see if FTC-TDF combination is safe in older adults who have early Alzheimer's disease. Participants will: * Take FTC-TDF combination or a placebo every day for 28 days. * Have 10 clinic visits over approximately 3 months. * Undergo blood tests, physical exams, cognitive testing, and scans of their brain.

Timeline

Start

2026-12

Primary completion

2028-07

Completion

2028-09

Publications

• Background Sullivan AC, Zuniga G, Ramirez P, Fernandez R, Wang CP, Li J, Davila L, Pelton K, Gomez S, Sohn C, Gonzalez E, Lopez-Cruzan M, Gonzalez DA, Parker A, Zilli E, de Erausquin GA, Seshadri S, Espinoza S, Musi N, Frost B. A Phase IIa clinical trial to evaluate the effects of anti-retroviral therapy in Alzheimer's disease (ART-AD). NPJ Dement. 2025;1(1):2. doi: 10.1038/s44400-024-00001-z. Epub 2025 Mar 12.
• Background Wahl D, Smith ME, McEntee CM, Cavalier AN, Osburn SC, Burke SD, Grant RA, Nerguizian D, Lark DS, Link CD, LaRocca TJ. The reverse transcriptase inhibitor 3TC protects against age-related cognitive dysfunction. Aging Cell. 2023 May;22(5):e13798. doi: 10.1111/acel.13798. Epub 2023 Mar 22.
• Background Wahl D, Grant RA, LaRocca TJ. The reverse transcriptase inhibitor 3TC modulates hippocampal transcriptome signatures of inflammation in tauopathy model mice. Exp Gerontol. 2024 Jul;192:112458. doi: 10.1016/j.exger.2024.112458. Epub 2024 May 21.
• Background Valles-Saiz L, Avila J, Hernandez F. Lamivudine (3TC), a Nucleoside Reverse Transcriptase Inhibitor, Prevents the Neuropathological Alterations Present in Mutant Tau Transgenic Mice. Int J Mol Sci. 2023 Jul 6;24(13):11144. doi: 10.3390/ijms241311144.
• Background Frost B, Dubnau J. The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders. Annu Rev Neurosci. 2024 Aug;47(1):123-143. doi: 10.1146/annurev-neuro-082823-020615. Epub 2024 Jul 1.
• Background Singh S, Borkar MR, Bhatt LK. Transposable Elements: Emerging Therapeutic Targets in Neurodegenerative Diseases. Neurotox Res. 2024 Jan 25;42(1):9. doi: 10.1007/s12640-024-00688-1.
• Background Roy N, Haq I, Ngo JC, Bennett DA, Teich AF, De Jager PL, Olah M, Sher F. Elevated expression of the retrotransposon LINE-1 drives Alzheimer's disease-associated microglial dysfunction. Acta Neuropathol. 2024 Nov 27;148(1):75. doi: 10.1007/s00401-024-02835-6.
• Background Mustafin RN, Khusnutdinova EK. Involvement of transposable elements in Alzheimer's disease pathogenesis. Vavilovskii Zhurnal Genet Selektsii. 2024 Apr;28(2):228-238. doi: 10.18699/vjgb-24-27.
• Background Evering TH, Marston JL, Gan L, Nixon DF. Transposable elements and Alzheimer's disease pathogenesis. Trends Neurosci. 2023 Mar;46(3):170-172. doi: 10.1016/j.tins.2022.12.003. Epub 2022 Dec 30.
• Background Yushkova E, Moskalev A. Transposable elements and their role in aging. Ageing Res Rev. 2023 Apr;86:101881. doi: 10.1016/j.arr.2023.101881. Epub 2023 Feb 10.

Drugs

Indications