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2000
Volume 32, Issue 30
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Alzheimer's disease (AD) remains a significant challenge in neurology, marked by progressive cognitive decline and neurodegeneration. Despite extensive research efforts, effective treatments are still lacking. Traditional drug discovery is often slow and costly, frequently resulting in limited success. Drug repurposing, which identifies new therapeutic uses for existing medications, has emerged as a promising approach to expedite AD treatment development. This review examines the potential of drug repurposing to transform AD therapy by utilizing the established safety profiles and known mechanisms of current drugs. We explore various repurposed drugs under investigation for AD, originally intended for cardiovascular, metabolic, and psychiatric conditions. Detailed discussions include how these drugs provide neuroprotective benefits by inhibiting amyloid-beta aggregation, reducing tau phosphorylation, and modulating neuroinflammation. Additionally, we emphasize the benefits of drug repurposing, such as shortened development timelines, lower costs, and increased chances of clinical success. By integrating current research findings, this review offers a thorough overview of the most promising repurposed drug candidates and their potential impact on AD treatment strategies. It stresses the importance of innovative approaches in AD research and calls for greater investment in drug repurposing initiatives. Through these strategies, we aim to accelerate the availability of effective treatments, providing renewed hope and a brighter future for those affected by this devastating disease.

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2025-01-23
2025-10-10
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References

  1. JahnH. Memory loss in Alzheimer’s disease.Dialogues Clin. Neurosci.201315444545410.31887/DCNS.2013.15.4/hjahn24459411
    [Google Scholar]
  2. CorbettA. BallardC. Information provision services in dementia care.Int. J. Older People Nurs.20116321722610.1111/j.1748‑3743.2011.00289.x21884487
    [Google Scholar]
  3. BallardC. AarslandD. CummingsJ. O’BrienJ. MillsR. MolinuevoJ.L. FladbyT. WilliamsG. DohertyP. CorbettA. SultanaJ. Drug repositioning and repurposing for Alzheimer disease.Nat. Rev. Neurol.2020161266167310.1038/s41582‑020‑0397‑432939050
    [Google Scholar]
  4. BallardC. CorbettA. JonesE.L. Dementia: Challenges and promising developments.Lancet Neurol.20111017910.1016/S1474‑4422(10)70304‑521163436
    [Google Scholar]
  5. HuY. YuK. WangG. ZhangD. ShiC. DingY. HongD. ZhangD. HeH. SunL. ZhengJ.N. SunS. QianF. Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell.Biochem. Pharmacol.201815028029210.1016/j.bcp.2018.02.02329475060
    [Google Scholar]
  6. BallardC. CorbettA. SharpS. Aligning the evidence with practice: NICE guidelines for drug treatment of Alzheimer’s disease.Expert Rev. Neurother.201111332732910.1586/ern.11.1321375436
    [Google Scholar]
  7. WimoA. GuerchetM. AliG.C. WuY.T. PrinaA.M. WinbladB. JönssonL. LiuZ. PrinceM. The worldwide costs of dementia 2015 and comparisons with 2010.Alzheimers Dement.20171311710.1016/j.jalz.2016.07.15027583652
    [Google Scholar]
  8. AnY. VarmaV.R. VarmaS. CasanovaR. DammerE. PletnikovaO. ChiaC.W. EganJ.M. FerrucciL. TroncosoJ. LeveyA.I. LahJ. SeyfriedN.T. Legido-QuigleyC. O’BrienR. ThambisettyM. Evidence for brain glucose dysregulation in Alzheimer’s disease.Alzheimers Dement.201814331832910.1016/j.jalz.2017.09.01129055815
    [Google Scholar]
  9. KwokM.K. LinS.L. SchoolingC.M. Re-thinking Alzheimer’s disease therapeutic targets using gene-based tests.EBioMedicine20183746147010.1016/j.ebiom.2018.10.00130314892
    [Google Scholar]
  10. ChanY.H. SchoolingC.M. ZhaoJ.V. YeungS.L.A. HaiJ.J. ThomasG.N. ChengK.K. JiangC.Q. WongY.K. AuK.W. TangC.S. CheungC.Y.Y. XuA. ShamP.C. LamT.H. LamK.S.L. TseH.F. Mendelian randomization analysis of vitamin D in the secondary prevention of hypertensive-diabetic subjects: Role of facilitating blood pressure control.Genes Nutr.2022171110.1186/s12263‑022‑00704‑z35093020
    [Google Scholar]
  11. WHO Director-General addresses G8 dementia summit.Available from: https://www.who.int/director-general/speeches/detail/who-director-general-addresses-g8-dementia-summit
  12. DeTureM.A. DicksonD.W. The neuropathological diagnosis of Alzheimer’s disease.Mol. Neurodegener.20191413210.1186/s13024‑019‑0333‑531375134
    [Google Scholar]
  13. MurrayM.E. Graff-RadfordN.R. RossO.A. PetersenR.C. DuaraR. DicksonD.W. Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: A retrospective study.Lancet Neurol.201110978579610.1016/S1474‑4422(11)70156‑921802369
    [Google Scholar]
  14. FanL. MaoC. HuX. ZhangS. YangZ. HuZ. SunH. FanY. DongY. YangJ. ShiC. XuY. New insights into the pathogenesis of Alzheimer’s disease.Front. Neurol.202010131210.3389/fneur.2019.0131231998208
    [Google Scholar]
  15. KarranE MerckenM. FGF23 and fetuin-a interaction in the liver and in the circulation.Int. J. Biol. Sci.2018145586598
    [Google Scholar]
  16. IttnerL.M. KeY.D. DelerueF. BiM. GladbachA. van EerselJ. WölfingH. ChiengB.C. ChristieM.J. NapierI.A. EckertA. StaufenbielM. HardemanE. GötzJ. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models.Cell2010142338739710.1016/j.cell.2010.06.03620655099
    [Google Scholar]
  17. RajmohanR. ReddyP.H. Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer’s disease neurons.J. Alzheimers Dis.201757497599910.3233/JAD‑16061227567878
    [Google Scholar]
  18. ChenG. XuT. YanY. ZhouY. JiangY. MelcherK. XuH.E. Amyloid beta: Structure, biology and structure-based therapeutic development.Acta Pharmacol. Sin.20173891205123510.1038/aps.2017.2828713158
    [Google Scholar]
  19. MehtaD. JacksonR. PaulG. ShiJ. SabbaghM. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015.Expert Opin. Investig. Drugs201726673573910.1080/13543784.2017.132386828460541
    [Google Scholar]
  20. YiannopoulouK.G. AnastasiouA.I. ZachariouV. PelidouS.H. Reasons for failed trials of disease-modifying treatments for Alzheimer disease and their contribution in recent research.Biomedicines2019749710.3390/biomedicines704009731835422
    [Google Scholar]
  21. TatulianS.A. Challenges and hopes for Alzheimer’s disease.Drug Discov. Today20222741027104310.1016/j.drudis.2022.01.01635121174
    [Google Scholar]
  22. PetersenR.C. Clinical practice. Mild cognitive impairment.N. Engl. J. Med.2011364232227223410.1056/NEJMcp091023721651394
    [Google Scholar]
  23. PetersenR.C. Mild cognitive impairment.Continuum2016222, Dementia40441810.1212/CON.000000000000031327042901
    [Google Scholar]
  24. JackC.R.Jr AlbertM.S. KnopmanD.S. McKhannG.M. SperlingR.A. CarrilloM.C. ThiesB. PhelpsC.H. Introduction to the recommendations from the national institute on aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease.Alzheimers Dement.20117325726210.1016/j.jalz.2011.03.00421514247
    [Google Scholar]
  25. Serrano-PozoA. FroschM.P. MasliahE. HymanB.T. Neuropathological alterations in Alzheimer disease.Cold Spring Harb. Perspect. Med.201111a00618910.1101/cshperspect.a00618922229116
    [Google Scholar]
  26. PanzaF LozuponeM LogroscinoG ImbimboBP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease.Nat. Rev. Neurol.2019152738810.1038/s41582‑018‑0116‑6
    [Google Scholar]
  27. HuangL.K. ChaoS.P. HuC.J. Clinical trials of new drugs for Alzheimer disease.J. Biomed. Sci.20202711810.1186/s12929‑019‑0609‑731906949
    [Google Scholar]
  28. BrodyD.L. HoltzmanD.M. Active and passive immunotherapy for neurodegenerative disorders.Annu. Rev. Neurosci.200831117519310.1146/annurev.neuro.31.060407.12552918352830
    [Google Scholar]
  29. LongJ.M. HoltzmanD.M. Alzheimer disease: An update on pathobiology and treatment strategies.Cell2019179231233910.1016/j.cell.2019.09.00131564456
    [Google Scholar]
  30. WilcockG.K. BlackS.E. HendrixS.B. ZavitzK.H. SwabbE.A. LaughlinM.A. Tarenflurbil Phase II Study investigators Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: A randomised phase II trial.Lancet Neurol.20087648349310.1016/S1474‑4422(08)70090‑518450517
    [Google Scholar]
  31. Alloway, S.; Sperling, R.; Gilman, S.A.; Fox, N.C.; Blennow, K.; Raskind, M.; Sabbagh, M.; Honig, L.S.; Doody, R.; Van Dyck, C.H.: Mulnard, R. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease.Neurology20097324206170
    [Google Scholar]
  32. AtharT. Al BalushiK. KhanS.A. Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease.Mol. Biol. Rep.20214875629564510.1007/s11033‑021‑06512‑934181171
    [Google Scholar]
  33. MoJ.J. LiJ. YangZ. LiuZ. FengJ.S. Efficacy and safety of anti-amyloid- β immunotherapy for Alzheimer’s disease: A systematic review and network meta-analysis.Ann. Clin. Transl. Neurol.201741293194210.1002/acn3.46929296624
    [Google Scholar]
  34. Van DyckCH. Anti-amyloid-β monoclonal antibodies for alzheimer's disease: Pitfalls and promise.Biol. Psychiatry2018834311319
    [Google Scholar]
  35. MullaneK. WilliamsM. Alzheimer’s disease (AD) therapeutics – 1: Repeated clinical failures continue to question the amyloid hypothesis of AD and the current understanding of AD causality.Biochem. Pharmacol.201815835937510.1016/j.bcp.2018.09.02630273553
    [Google Scholar]
  36. JeremicD. Jiménez-DíazL. Navarro-LópezJ.D. Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: A systematic review.Ageing Res. Rev.20217210149610.1016/j.arr.2021.10149634687956
    [Google Scholar]
  37. CummingsJ. RitterA. ZhongK. Clinical trials for disease-modifying therapies in Alzheimer’s disease: A primer, lessons learned, and a blueprint for the future.J. Alzheimers Dis.201864s1Suppl. 1S3S2210.3233/JAD‑17990129562511
    [Google Scholar]
  38. SirotaM. DudleyJ.T. KimJ. ChiangA.P. MorganA.A. Sweet-CorderoA. SageJ. ButteA.J. Discovery and preclinical validation of drug indications using compendia of public gene expression data.Sci. Transl. Med.201139696ra7710.1126/scitranslmed.300131821849665
    [Google Scholar]
  39. GarberK. Genentech’s Alzheimer’s antibody trial to study disease prevention.Nat. Biotechnol.201230873173210.1038/nbt0812‑73122871696
    [Google Scholar]
  40. GodyńJ. JończykJ. PanekD. MalawskaB. Therapeutic strategies for Alzheimer’s disease in clinical trials.Pharmacol. Rep.201668112713810.1016/j.pharep.2015.07.00626721364
    [Google Scholar]
  41. ClinicalTrials.gov [Internet].Available from: https://clinicaltrials.gov/
  42. ISRCTN Registry.Available from: https://www.isrctn.com/
  43. CorriveauR.A. KoroshetzW.J. GladmanJ.T. JeonS. BabcockD. BennettD.A. CarmichaelS.T. DickinsonS.L.J. DicksonD.W. EmrM. FillitH. GreenbergS.M. HuttonM.L. KnopmanD.S. ManlyJ.J. MarderK.S. MoyC.S. PhelpsC.H. ScottP.A. SeeleyW.W. SieberB.A. SilverbergN.B. SutherlandM.L. TaylorA. TorborgC.L. WaddyS.P. GubitzA.K. HoltzmanD.M. Alzheimer’s disease–related dementias summit 2016: National research priorities.Neurology201789232381239110.1212/WNL.000000000000471729117955
    [Google Scholar]
  44. BrownN. CambruzziJ. CoxP.J. DaviesM. DunbarJ. PlumbleyD. SellwoodM.A. SimA. Williams-JonesB.I. ZwierzynaM. SheppardD.W. Big data in drug discovery.Prog. Med. Chem.201857127735610.1016/bs.pmch.2017.12.00329680150
    [Google Scholar]
  45. RudrapalM KhairnarSJ JadhavAG. Drug repurposing (DR): An emerging approach in drug discovery.Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic ApplicationsIntechOpen2020
    [Google Scholar]
  46. SaraeiP. AsadiI. KakarM.A. Moradi-KorN. The beneficial effects of metformin on cancer prevention and therapy: A comprehensive review of recent advances.Cancer Manag. Res.2019113295331310.2147/CMAR.S20005931114366
    [Google Scholar]
  47. ChaY. ErezT. ReynoldsI.J. KumarD. RossJ. KoytigerG. KuskoR. ZeskindB. RissoS. KaganE. PapapetropoulosS. GrossmanI. LaifenfeldD. Drug repurposing from the perspective of pharmaceutical companies.Br. J. Pharmacol.2018175216818010.1111/bph.1379828369768
    [Google Scholar]
  48. DuboisB. HampelH. FeldmanH.H. ScheltensP. AisenP. AndrieuS. BakardjianH. BenaliH. BertramL. BlennowK. BroichK. CavedoE. CrutchS. DartiguesJ.F. DuyckaertsC. EpelbaumS. FrisoniG.B. GauthierS. GenthonR. GouwA.A. HabertM.O. HoltzmanD.M. KivipeltoM. ListaS. MolinuevoJ.L. O’BryantS.E. RabinoviciG.D. RoweC. SallowayS. SchneiderL.S. SperlingR. TeichmannM. CarrilloM.C. CummingsJ. JackC.R.Jr. Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer’s Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria.Alzheimers Dement.201612329232310.1016/j.jalz.2016.02.00227012484
    [Google Scholar]
  49. CummingsJ. AisenP.S. DuBoisB. FrölichL. JackC.R.Jr JonesR.W. MorrisJ.C. RaskinJ. DowsettS.A. ScheltensP. Drug development in Alzheimer’s disease: The path to 2025.Alzheimers Res. Ther.2016813910.1186/s13195‑016‑0207‑927646601
    [Google Scholar]
  50. UlemanJ.F. MelisR.J.F. HoekstraA.G. Olde RikkertM.G.M. QuaxR. Australian Imaging, Biomarker and Lifestyle study of Aging and Alzheimer’s Disease Neuroimaging Initiative studies Exploring the potential impact of multi- factor precision interventions in Alzheimer’s disease with system dynamics.J. Biomed. Inform.2023145July10446210.1016/j.jbi.2023.10446237516375
    [Google Scholar]
  51. JourdanJ.P. BureauR. RochaisC. DallemagneP. Drug repositioning: A brief overview.J. Pharm. Pharmacol.20207291145115110.1111/jphp.1327332301512
    [Google Scholar]
  52. ShoaibM. KamalM.A. RizviS.M.D. Repurposed drugs as potential therapeutic candidates for the management of Alzheimer’s disease.Curr. Drug Metab.201718984285228595531
    [Google Scholar]
  53. ArboB.D. SchimithL.E. Goulart dos SantosM. HortM.A. Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation.Eur. J. Pharmacol.202291917480010.1016/j.ejphar.2022.17480035131314
    [Google Scholar]
  54. HuaY. DaiX. XuY. XingG. LiuH. LuT. ChenY. ZhangY. Drug repositioning: Progress and challenges in drug discovery for various diseases.Eur. J. Med. Chem.202223411423910.1016/j.ejmech.2022.11423935290843
    [Google Scholar]
  55. HonigL.S. BoydC.D. Treatment of Alzheimer’s disease: Current management and experimental therapeutics.Curr. Transl. Geriatr. Exp. Gerontol. Rep.20132317418110.1007/s13670‑013‑0056‑324093080
    [Google Scholar]
  56. RoachJ.C. HaraJ. FridmanD. LovejoyJ.C. JadeK. HeimL. RomansikR. SwietlikowskiA. PhillipsS. RapozoM.K. ShayM.A. FischerD. FunkC. DillL. Brant-ZawadzkiM. HoodL. ShankleW.R. The coaching for cognition in Alzheimer’s (COCOA) trial: Study design.Alzheimers Dement. (N. Y.)202281e1231810.1002/trc2.1231835910672
    [Google Scholar]
  57. GouillyD RafiqM NogueiraL SalabertAS PayouxP PéranP. Beyond the amyloid cascade: An update of Alzheimer’s disease pathophysiology.Rev. Neurol.20231798812830
    [Google Scholar]
  58. YiannopoulouK.G. PapageorgiouS.G. Current and future treatments in Alzheimer disease: An update.J. Cent. Nerv. Syst. Dis.2020121177/117957352090739710.1177/117957352090739732165850
    [Google Scholar]
  59. BreijyehZ KaramanR Muñoz-TorreroD DembinskiR. Comprehensive review on Alzheimer’s disease: Causes and treatment.Molecules202025245789578910.3390/molecules2524578933302541
    [Google Scholar]
  60. ArafahA. KhatoonS. RasoolI. KhanA. RatherM.A. AbujabalK.A. FaqihY.A.H. RashidH. RashidS.M. Bilal AhmadS. AlexiouA. RehmanM.U. The future of precision medicine in the cure of Alzheimer’s disease.Biomedicines202311233510.3390/biomedicines1102033536830872
    [Google Scholar]
  61. IsaacsonR.S. GanzerC.A. HristovH. HackettK. CaesarE. CohenR. KachkoR. Meléndez-CabreroJ. RahmanA. ScheyerO. HwangM.J. BerkowitzC. HendrixS. MurebM. SchelkeM.W. MosconiL. SeifanA. KrikorianR. The clinical practice of risk reduction for Alzheimer’s disease: A precision medicine approach.Alzheimers Dement.201814121663167310.1016/j.jalz.2018.08.00430446421
    [Google Scholar]
  62. AisenP.S. SchaferK.A. GrundmanM. PfeifferE. SanoM. DavisK.L. FarlowM.R. JinS. ThomasR.G. ThalL.J. Alzheimer’s Disease Cooperative Study Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression: A randomized controlled trial.JAMA2003289212819282610.1001/jama.289.21.281912783912
    [Google Scholar]
  63. KrishnamurthyN. GrimshawA.A. AxsonS.A. ChoeS.H. MillerJ.E. Drug repurposing: A systematic review on root causes, barriers and facilitators.BMC Health Serv. Res.202222197010.1186/s12913‑022‑08272‑z35906687
    [Google Scholar]
  64. PeronR. VatanabeI.P. ManzineP.R. CaminsA. CominettiM.R. Alpha-secretase ADAM10 regulation: Insights into Alzheimer’s disease treatment.Pharmaceutics201811112
    [Google Scholar]
  65. AliM.M. GhouriR.G. AnsA.H. AkbarA. ToheedA. Recommendations for anti-inflammatory treatments in Alzheimer’s disease: A comprehensive review of the literature.Cureus2019115e462010.7759/cureus.462031312547
    [Google Scholar]
  66. BauzonJ. LeeG. CummingsJ. Repurposed agents in the Alzheimer’s disease drug development pipeline.Alzheimers Res. Ther.20201219810.1186/s13195‑020‑00662‑x32807237
    [Google Scholar]
  67. MiculasD.C. NegruP.A. BungauS.G. BehlT. HassanS.S. TitD.M. Pharmacotherapy evolution in Alzheimer’s disease: Current framework and relevant directions.Cells202212113110.3390/cells1201013136611925
    [Google Scholar]
  68. ZhangJ. ZhangY. WangJ. XiaY. ZhangJ. ChenL. Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies.Signal Transduct. Target Ther.20249113510.1038/s41392‑024‑01911‑3
    [Google Scholar]
  69. LogingW. Rodriguez-EstebanR. HillJ. FreemanT. MigliettaJ. Cheminformatic/bioinformatic analysis of large corporate databases: Application to drug repurposing.Drug Discov. Today Ther. Strateg.201183-410911610.1016/j.ddstr.2011.06.004
    [Google Scholar]
  70. ParvathaneniV. KulkarniN.S. MuthA. GuptaV. Drug repurposing: A promising tool to accelerate the drug discovery process.Drug Discov. Today201924102076208510.1016/j.drudis.2019.06.01431238113
    [Google Scholar]
  71. SavvaK. ZachariouM. BourdakouM.M. DietisN. SpyrouG.M. Network-based stage-specific drug repurposing for Alzheimer’s disease.Comput. Struct. Biotechnol. J.2022201427143810.1016/j.csbj.2022.03.01335386099
    [Google Scholar]
  72. RajputA. ThakurA. RastogiA. ChoudhuryS. KumarM. Computational identification of repurposed drugs against viruses causing epidemics and pandemics via drug- target network analysis.Comput. Biol. Med.202113610467710.1016/j.compbiomed.2021.10467734332351
    [Google Scholar]
  73. YeQ. HsiehC.Y. YangZ. KangY. ChenJ. CaoD. HeS. HouT. A unified drug–target interaction prediction framework based on knowledge graph and recommendation system.Nat. Commun.2021121677510.1038/s41467‑021‑27137‑334811351
    [Google Scholar]
  74. JudgeA. GarrigaC. ArdenN. Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients.Alzheimers Dement.20173461262110.1016/j.trci.2017.10.002
    [Google Scholar]
  75. XuM. LeeE.M. WenZ. ChengY. HuangW.K. QianX. TcwJ. KouznetsovaJ. OgdenS.C. HammackC. JacobF. NguyenH.N. ItkinM. HannaC. ShinnP. AllenC. MichaelS.G. SimeonovA. HuangW. ChristianK.M. GoateA. BrennandK.J. HuangR. XiaM. MingG. ZhengW. SongH. TangH. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.Nat. Med.201622101101110710.1038/nm.418427571349
    [Google Scholar]
  76. WilliamsG. GattA. ClarkeE. Drug repurposing for Alzheimer's disease based on transcriptional profiling of human iPSC-derived cortical neurons.Transl. Psychiatry201991220220
    [Google Scholar]
  77. KillickR. ElliottC. RibeE. BroadstockM. BallardC. AarslandD. Neurodegenerative disease associated pathways in brain of the triple transgenic Alzheimer’s model are reversed in vivo following two weeks peripheral administration.biorxiv202210.1101/2022.09.30.510301
    [Google Scholar]
  78. KhanA. CorbettA. BallardC. Emerging treatments for Alzheimer’s disease for non-amyloid and non-tau targets.Expert Rev. Neurother.201717768369510.1080/14737175.2017.132681828490260
    [Google Scholar]
  79. SnyderG.L. VanoverK.E. ZhuH. MillerD.B. O’CallaghanJ.P. TomeschJ. LiP. ZhangQ. KrishnanV. HendrickJ.P. NestlerE.J. DavisR.E. WennogleL.P. MatesS. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.Psychopharmacology2015232360562110.1007/s00213‑014‑3704‑125120104
    [Google Scholar]
  80. AtriA. FrölichL. BallardC. TariotP.N. MolinuevoJ.L. BonevaN. WindfeldK. RaketL.L. CummingsJ.L. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: Three randomized clinical trials.JAMA2018319213014210.1001/jama.2017.2037329318278
    [Google Scholar]
  81. HowardR. ZubkoO. BradleyR. Minocycline at 2 different dosages vs. placebo for patients with mild Alzheimer disease: A randomized clinical trial.JAMA. Neurol.2020772164174
    [Google Scholar]
  82. LawlorB. SeguradoR. KennellyS. Olde RikkertM.G.M. HowardR. PasquierF. Börjesson-HansonA. TsolakiM. LuccaU. MolloyD.W. CoenR. RiepeM.W. KálmánJ. KennyR.A. CreggF. O’DwyerS. WalshC. AdamsJ. BanziR. BreuilhL. DalyL. HendrixS. AisenP. GaynorS. SheikhiA. TaekemaD.G. VerheyF.R. NemniR. NobiliF. FranceschiM. FrisoniG. ZanettiO. KonstaA. AnastasiosO. NenopoulouS. Tsolaki-TagarakiF. PakaskiM. DereeperO. de la SayetteV. SénéchalO. LavenuI. DevendevilleA. CalaisG. CrawfordF. MullanM. NILVAD Study Group Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.PLoS Med.2018159e100266010.1371/journal.pmed.100266030248105
    [Google Scholar]
  83. KehoeP.G. BlairP.S. HowdenB. ThomasD.L. MaloneI.B. HorwoodJ. The rationale and design of the reducing pathology in Alzheimer's disease through angiotensin targeting (RADAR) trial.J. Alzheimers. Dis2018612803814
    [Google Scholar]
  84. SongY. ChenX. WangL.Y. GaoW. ZhuM.J. Mei-Jia ZhuC. Rho kinase inhibitor fasudil protects against β-amyloid-induced hippocampal neurodegeneration in rats.CNS Neurosci. Ther.201319860361010.1111/cns.1211623638992
    [Google Scholar]
  85. KillickR. RibeE. Al-ShawiR. MalikB. Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.Mol. Psychiatry20141918898
    [Google Scholar]
  86. ElliottC. RojoA. RibeE. BroadstockM. A role for APP in Wnt signalling links synapse loss with β-amyloid production.Transl. Psychiatry201881179179
    [Google Scholar]
  87. SantanaS. RecueroM. BullidoM. Herpes simplex virus type I induces the accumulation of intracellular β-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells.Neurobiol. Aging2012332430.e1943310.1016/j.neurobiolaging.2010.12.010
    [Google Scholar]
  88. LerchundiR. NeiraR. ValdiviaS. Tau cleavage at D421 by caspase-3 is induced in neurons and astrocytes infected with herpes simplex virus type 1.J. Alzheimers. Dis201123351352010.3233/JAD‑2010‑101386
    [Google Scholar]
  89. SiZ. Stem cell therapies in Alzheimer's disease: Applications for disease modeling.J. Pharmacol. Exp. Ther.20213772207217
    [Google Scholar]
  90. SharmaK. Cholinesterase inhibitors as Alzheimer’s therapeutics (Review).Mol. Med. Rep.20192021479148731257471
    [Google Scholar]
  91. LiptonS. Calcium, free radicals and excitotoxins in neuronal apoptosis.Cell Calcium1998Feb-Mar232-316517110.1016/s0143‑4160(98)90115‑4
    [Google Scholar]
  92. WieseL.K. LinglerJ. LindauerA. Alzheimer’s disease and Lewy body dementia: Discerning the differences: Assessment is key for optimal management.Am. Nurse J.2021161101735815334
    [Google Scholar]
  93. LevineM.J. Empagliflozin for type 2 diabetes mellitus: An overview of phase 3 clinical trials.Curr. Diabetes Rev.201713440542327296042
    [Google Scholar]
  94. GuanL. YangH. CaiY. SunL. DiP. LiW. LiuG. TangY. ADMET-score – A comprehensive scoring function for evaluation of chemical drug-likeness.MedChemComm201910114815710.1039/C8MD00472B30774861
    [Google Scholar]
  95. KalitaJ. ChetiaD. Chemistry, MRM design, synthesis, antimalarial activity and docking study of 7-Chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines.Med. Chem.2020167928937
    [Google Scholar]
  96. Carracedo-ReboredoP. Liñares-BlancoJ. Rodríguez-FernándezN. CedrónF. NovoaF.J. CarballalA. MaojoV. PazosA. Fernandez-LozanoC. A review on machine learning approaches and trends in drug discovery.Comput. Struct. Biotechnol. J.2021194538455810.1016/j.csbj.2021.08.01134471498
    [Google Scholar]
  97. DigheS.N. TippanaM. van AkkerS. ColletT.A. Structure-based scaffold repurposing toward the discovery of novel cholinesterase inhibitors.ACS Omega2020548309713097910.1021/acsomega.0c0384833324805
    [Google Scholar]
  98. DaraS. DhamercherlaS. JadavS.S. BabuC.H.M. AhsanM.J. Machine learning in drug discovery: A review.Artif. Intell. Rev.20225531947199910.1007/s10462‑021‑10058‑434393317
    [Google Scholar]
  99. OlaruA.M. VasilacheV. DanacR. MangalagiuI.I. Antimycobacterial activity of nitrogen heterocycles derivatives: 7-(pyridine-4-yl)-indolizine derivatives. Part VII 8–12.J. Enzyme Inhib. Med. Chem.20173211291129810.1080/14756366.2017.137548329072097
    [Google Scholar]
  100. VenugopalaK.N. Al-Shar’iN.A. DahabiyehL.A. HouraniW. DebP.K. PillayM. Abu-IrmailehB. BustanjiY. ChandrashekharappaS. TratratC. AttimaradM. NairA.B. SreeharshaN. ShinuP. HarounM. KandeelM. BalgonameA.A. VenugopalaR. MorsyM.A. Antitubercular, cytotoxicity, and computational target validation of dihydroquinazolinone derivatives.Antibiotics202211783110.3390/antibiotics1107083135884084
    [Google Scholar]
  101. Sharifi-RadJ. RapposelliS. SestitoS. Herrera-BravoJ. Arancibia-DiazA. SalazarL.A. YeskaliyevaB. BeyatliA. Leyva-GómezG. González-ContrerasC. GürerE.S. MartorellM. CalinaD. Multi-target mechanisms of phytochemicals in Alzheimer’s disease: Effects on oxidative stress, neuroinflammation and protein aggregation.J. Pers. Med.2022129151510.3390/jpm1209151536143299
    [Google Scholar]
  102. dos Santos GuilhermeM. StoyeN.M. Rose-JohnS. GarbersC. FellgiebelA. EndresK. The synthetic retinoid acitretin increases IL-6 in the central nervous system of Alzheimer disease model mice and human patients.Front. Aging Neurosci.201911JUL18210.3389/fnagi.2019.0018231396076
    [Google Scholar]
  103. KumarN. GahlawatA. KumarR.N. SinghY.P. ModiG. GargP. Drug repurposing for Alzheimer’s disease: in silico and in vitro investigation of FDA-approved drugs as acetylcholinesterase inhibitors.J. Biomol. Struct. Dyn.20224072878289210.1080/07391102.2020.184405433170091
    [Google Scholar]
  104. IqbalU.H. ZengE. PasinettiG.M. The use of antimicrobial and antiviral drugs in Alzheimer’s disease.Int. J. Mol. Sci.20202114492010.3390/ijms2114492032664669
    [Google Scholar]
  105. GongC.X. DaiC.L. LiuF. IqbalK. Multi-targets: An unconventional drug development strategy for Alzheimer’s disease.Front. Aging Neurosci.20221483764910.3389/fnagi.2022.83764935222001
    [Google Scholar]
  106. SlanziA. IannotoG. RossiB. ZenaroE. ConstantinG. In vitro models of neurodegenerative diseases.Front. Cell Dev. Biol.2020832810.3389/fcell.2020.0032832528949
    [Google Scholar]
  107. BlaikieL. KayG. MacielP. Kong Thoo LinP. Experimental modelling of Alzheimer’s disease for therapeutic screening.Eur. J. Med. Chem. Rep.2022510004410.1016/j.ejmcr.2022.100044
    [Google Scholar]
  108. SallowayS.P. SevingyJ. BudurK. PedersonJ.T. DeMattosR.B. Von RosenstielP. PaezA. EvansR. WeberC.J. HendrixJ.A. WorleyS. BainL.J. CarrilloM.C. Advancing combination therapy for Alzheimer’s disease.Alzheimers Dement.202061e1207310.1002/trc2.1207333043108
    [Google Scholar]
  109. OpreaT.I. MestresJ. Drug repurposing: Far beyond new targets for old drugs.AAPS J.201214475976310.1208/s12248‑012‑9390‑122826034
    [Google Scholar]
  110. TysonR.J. ParkC.C. PowellJ.R. PattersonJ.H. WeinerD. WatkinsP.B. GonzalezD. Precision dosing priority criteria: Drug, disease, and patient population variables.Front. Pharmacol.20201142010.3389/fphar.2020.0042032390828
    [Google Scholar]
  111. TsolakiM. FountoulakisC. PavlopoulosI. ChatziE. KazisA. Prevalence and incidence of Alzheimers disease and other dementing disorders in Pylea, Greece.Am. J. Alzheimers Dis. Other Demen.1999143138148
    [Google Scholar]
  112. AndrieuS. ColeyN. LovestoneS. AisenP.S. VellasB. Prevention of sporadic Alzheimer’s disease: Lessons learned from clinical trials and future directions.Lancet Neurol.201514992694410.1016/S1474‑4422(15)00153‑226213339
    [Google Scholar]
  113. QiuC. KivipeltoM. von StraussE. Epidemiology of Alzheimer’s disease: Occurrence, determinants, and strategies toward intervention.Dialogues Clin. Neurosci.200911211112810.31887/DCNS.2009.11.2/cqiu19585947
    [Google Scholar]
  114. TzourioC. Hypertension, cognitive decline, and dementia: An epidemiological perspective.Dialogues Clin. Neurosci.200791617010.31887/DCNS.2007.9.1/ctzourio17506226
    [Google Scholar]
  115. LiN LeeA WhitmerR KivipeltoM BmjEL. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis.BMJ2010340b5465
    [Google Scholar]
  116. WeberF.J. LatshangT.D. BlumM.R. KohlerM. WertliM.M. Prognostic factors, disease course, and treatment efficacy in Duchenne muscular dystrophy: A systematic review and meta-analysis.Muscle Nerve202266446247010.1002/mus.2768235860996
    [Google Scholar]
  117. BarrP. OwenC. RobakT. Up to 8-year follow-up from RESONATE-2: First-line ibrutinib treatment for patients with chronic lymphocytic leukemia.Blood Adv.202261134403450
    [Google Scholar]
  118. AbrahamH.M.A. WhiteC.M. WhiteW.B. The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases.Drug Saf.2015381335410.1007/s40264‑014‑0239‑725416320
    [Google Scholar]
  119. Guideline for the pharmacological treatment of hypertension in adults.World Health OrganizationGeneva2021240114578
    [Google Scholar]
  120. OumataN. LuK. TengY. CavéC. Molecular mechanisms in Alzheimer’s disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules.Elsevier2022155113769
    [Google Scholar]
  121. KomuraT. AokiM. KotouraS. Protective effect of Lactococcus laudensis and Pediococcus parvulus against neuropathy due to amyloid-beta in Caenorhabditis elegansElsevier2022
    [Google Scholar]
  122. ZhaoW. WangJ. HoL. Identification of antihypertensive drugs which inhibit amyloid-beta protein oligomerization.J. Alzheimers Dis.2009161495710.3233/JAD‑2009‑0925
    [Google Scholar]
  123. AnekondaT. QuinnJ. HarrisC. L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease.Neurobiol. Dis.2011411627010.1016/j.nbd.2010.08.020
    [Google Scholar]
  124. ParisD. BachmeierC. PatelN. QuadrosA. VolmarC.H. LaporteV. GaneyJ. Beaulieu-AbdelahadD. Ait-GhezalaG. CrawfordF. MullanM.J. Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier.Mol. Med.2011173-414916210.2119/molmed.2010.0018021170472
    [Google Scholar]
  125. MoloneyA. GriffinR. TimmonsS. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signallingElsevier2010312224243
    [Google Scholar]
  126. SchrijversE WittemanJ NeurologyES Insulin metabolism and the risk of Alzheimer disease: The rotterdam study.Neurology2010752219821987
    [Google Scholar]
  127. MoloneyA.M. GriffinR.J. TimmonsS. O’ConnorR. RavidR. O’NeillC. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling.Neurobiol. Aging201031222424310.1016/j.neurobiolaging.2008.04.00218479783
    [Google Scholar]
  128. HamiltonA. PattersonS. PorterD. GaultV.A. HolscherC. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain.J. Neurosci. Res.201189448148910.1002/jnr.2256521312223
    [Google Scholar]
  129. McClean, P.L.: Parthasarathy, V.: Gault, V.: Holscher, C. liraglutide, a novel glp-1 analogue, prevents the impairment of learning and ltp and plaque formation in an app/ps-1 mouse model of Alzheimer's disease.J. Irish. Med. Sci.2011180218
    [Google Scholar]
  130. GarberA. HandelsmanY. GrunbergerG. PracticeD.E.E. Consensus statement by the american association of clinical endocrinologists and American college of endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary.Endocr. Pract.202026110713910.4158/CS‑2019‑0472
    [Google Scholar]
  131. GarberA. AbrahamsonM. BarzilayJ. PracticeL.B.E. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary.Endocr. Pract.20192516910010.4158/CS‑2018‑0535
    [Google Scholar]
  132. GarberA.J. AbrahamsonM.J. BarzilayJ.I. BlondeL. BloomgardenZ.T. BushM.A. Dagogo-JackS. DeFronzoR.A. EinhornD. FonsecaV.A. GarberJ.R. GarveyW.T. GrunbergerG. HandelsmanY. HirschI.B. JellingerP.S. McGillJ.B. MechanickJ.I. RosenblitP.D. UmpierrezG.E. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2018 executive summary.Endocr. Pract.20182419112110.4158/CS‑2017‑015329368965
    [Google Scholar]
  133. DingY. QiaoA. WangZ. GoodwinJ.S. LeeE.S. BlockM.L. AllsbrookM. McDonaldM.P. FanG.H. Retinoic acid attenuates β-amyloid deposition and rescues memory deficits in an Alzheimer’s disease transgenic mouse model.J. Neurosci.20082845116221163410.1523/JNEUROSCI.3153‑08.200818987198
    [Google Scholar]
  134. TippmannF. HundtJ. SchneiderA. EndresK. FahrenholzF. Up-regulation of the α-secretase ADAM10 by retinoic acid receptors and acitretin.FASEB J.20092361643165410.1096/fj.08‑12139219144697
    [Google Scholar]
  135. JarvisC.I. GoncalvesM.B. ClarkeE. DogruelM. KalindjianS.B. ThomasS.A. MadenM. CorcoranJ.P.T. Retinoic acid receptor-α signalling antagonizes both intracellular and extracellular amyloid-β production and prevents neuronal cell death caused by amyloid-β.Eur. J. Neurosci.20103281246125510.1111/j.1460‑9568.2010.07426.x20950278
    [Google Scholar]
  136. QiaoA. LiJ. HuY. WangJ. ReportsZ.Z.I.N. Reduction BACE1 expression via suppressing NF-κB mediated signaling by Tamibarotene in a mouse model of Alzheimer's disease.IBRO Neurosci. Rep.20211015316010.1016/j.ibneur.2021.02.004
    [Google Scholar]
  137. CramerP.E. CirritoJ.R. WessonD.W. LeeC.Y.D. KarloJ.C. ZinnA.E. CasaliB.T. RestivoJ.L. GoebelW.D. JamesM.J. BrundenK.R. WilsonD.A. LandrethG.E. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.Science201233560751503150610.1126/science.121769722323736
    [Google Scholar]
  138. DeMattosR. PattersonB. FaganA. MorrisJ. Human ApoE isoforms differentially regulate brain amyloid-b peptide clearance.Sci. Transl. Med.201138989ra57
    [Google Scholar]
  139. SoP. YipP. BuntingS. WongL. Interactions between retinoic acid, nerve growth factor and sonic hedgehog signalling pathways in neurite outgrowth.Dev Biol.2006298116717510.1016/j.ydbio.2006.06.027
    [Google Scholar]
  140. LiuC.C. MurrayM.E. LiX. ZhaoN. WangN. HeckmanM.G. ShueF. MartensY. LiY. RaulinA.C. RosenbergC.L. DossS.V. ZhaoJ. WrenM.C. JiaL. RenY. IkezuT.C. LuW. FuY. CaulfieldT. TrottierZ.A. KnightJ. ChenY. LinaresC. WangX. KurtiA. AsmannY.W. WszolekZ.K. SmithG.E. VemuriP. KantarciK. KnopmanD.S. LoweV.J. JackC.R.Jr ParisiJ.E. FermanT.J. BoeveB.F. Graff-RadfordN.R. PetersenR.C. YounkinS.G. FryerJ.D. WangH. HanX. FriedenC. DicksonD.W. RossO.A. BuG. APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia.Sci. Transl. Med.202113613eabc937510.1126/scitranslmed.abc937534586832
    [Google Scholar]
  141. KongF. WuT. DaiJ. ZhaiZ. CaiJ. ZhuZ. XuY. SunT. Glucagon-like peptide 1 (GLP-1) receptor agonists in experimental Alzheimer’s disease models: A systematic review and meta-analysis of preclinical studies.Front. Pharmacol.202314120520710.3389/fphar.2023.120520737771725
    [Google Scholar]
  142. WrightJ. Brain renin-angiotensin-a new look at an old system.Prog. Neurobiol.20119514967
    [Google Scholar]
  143. WangJ. HoL. ChenL. ZhaoZ. Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease.J. Clin. Invest.20071171133933402
    [Google Scholar]
  144. FerringtonL. MinersJ. Angiotensin II-inhibiting drugs have no effect on intraneuronal Aβ or oligomeric Aβ levels in a triple transgenic mouse model of Alzheimer's disease.Am. J. Transl. Res.201132197208
    [Google Scholar]
  145. HemmingM. SelkoeD. Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease.Neurobiol. Dis.2007261273281
    [Google Scholar]
  146. AsherS. PrieferR. Alzheimer’s disease failed clinical trials.Life Sci.202230612086110.1016/j.lfs.2022.12086135932841
    [Google Scholar]
  147. DengZ. JiangJ. WangJ. PanD. ZhuY. LiH. ZhangX. LiuX. XuY. LiY. TangY. Alzheimer’s Disease Neuroimaging Initiative† Angiotensin receptor blockers are associated with a lower risk of progression from mild cognitive impairment to dementia.Hypertension202279102159216910.1161/HYPERTENSIONAHA.122.1937835766029
    [Google Scholar]
  148. BildW. VasincuA. RusuR.N. AbabeiD.C. StanaA.B. StanciuG.D. SavuB. BildV. Impact of the renin-angiotensin system on the pathogeny and pharmacotherapeutics of neurodegenerative diseases.Biomolecules20221210142910.3390/biom1210142936291638
    [Google Scholar]
  149. KivipeltoM. PalmerK. HoangT.D. YaffeK. Trials and treatments for vascular brain health: Risk factor modification and cognitive outcomes.Stroke202253244445610.1161/STROKEAHA.121.03261435000424
    [Google Scholar]
  150. GouveiaF. CaminsA. EttchetoM. BickerJ. FalcãoA. CruzM.T. FortunaA. Targeting brain renin-angiotensin system for the prevention and treatment of Alzheimer’s disease: Past, present and future.Ageing Res. Rev.20227710161210.1016/j.arr.2022.10161235346852
    [Google Scholar]
  151. GanzT. FainsteinN. Ben-HurT. When the infectious environment meets the AD brain.Mol. Neurodegener.20221715310.1186/s13024‑022‑00559‑335986296
    [Google Scholar]
  152. DanielyanL. KleinR. HansonL.R. BuadzeM. SchwabM. GleiterC.H. FreyW.H. Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease.Rejuvenation Res.2010132-319520110.1089/rej.2009.094420370487
    [Google Scholar]
  153. IwasakiK. EgashiraN. Nilvadipine prevents the impairment of spatial memory induced by cerebral ischemia combined with beta-amyloid in rats.Biol. Pharm. Bull.200730469870110.1248/bpb.30.698
    [Google Scholar]
  154. MartinD.M. McClintockS.M. ForsterJ.J. LoT.Y. LooC.K. Cognitive enhancing effects of rTMS administered to the prefrontal cortex in patients with depression: A systematic review and meta-analysis of individual task effects.Depress. Anxiety201734111029103910.1002/da.2265828543994
    [Google Scholar]
  155. CopenhaverP. A translational continuum of model systems for evaluating treatment strategies in Alzheimer's disease: Isradipine as a candidate drug.Dis. Model. Mech.20114563464810.1242/dmm.006841
    [Google Scholar]
  156. López-ArrietaJ.M. BirksJ. Nimodipine for primary degenerative, mixed and vascular dementia.Cochrane Database Syst. Rev.20023CD00014712137606
    [Google Scholar]
  157. KennellyS. AbdullahL. KennyR.A. MathuraV. LuisC.A. MouzonB. CrawfordF. MullanM. LawlorB. Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer’s patients—an open-label trial.Int. J. Geriatr. Psychiatry201227441542210.1002/gps.273521560164
    [Google Scholar]
  158. QinM. WuJ. ZhouQ. LiangZ. SuY. Global cognitive effects of second-generation antidepressants in patients with Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials.J. Psychiatr. Res.202215537137910.1016/j.jpsychires.2022.09.03936182766
    [Google Scholar]
  159. KhachaturianA ZandiP. Antihypertensive medication use and incident Alzheimer disease: The cache county study.Arch. Neurol.200663568669210.1001/archneur.63.5.noc60013
    [Google Scholar]
  160. HampelH. VergalloA. AguilarL.F. BendaN. BroichK. CuelloA.C. CummingsJ. DuboisB. FederoffH.J. FiandacaM. GenthonR. HaberkampM. KarranE. MapstoneM. PerryG. SchneiderL.S. WelikovitchL.A. WoodcockJ. BaldacciF. ListaS. Alzheimer Precision Medicine Initiative (APMI) Precision pharmacology for Alzheimer’s disease.Pharmacol. Res.201813033136510.1016/j.phrs.2018.02.01429458203
    [Google Scholar]
  161. SimS. WongN. Nanotechnology and its use in imaging and drug delivery (Review).Biomed. Rep.20211454210.3892/br.2021.141833728048
    [Google Scholar]
  162. LiL. HeR. YanH. LengZ. ZhuS. GuZ. Nanotechnology for the diagnosis and treatment of Alzheimer’s disease: A bibliometric analysis.Nano Today20224710165410.1016/j.nantod.2022.101654
    [Google Scholar]
  163. StewartS.A. Domínguez-RoblesJ. DonnellyR.F. LarrañetaE. Implantable polymeric drug delivery devices: Classification, manufacture, materials, and clinical applications.Polymers20181012137910.3390/polym1012137930961303
    [Google Scholar]
  164. StewartS. Domínguez-RoblesJ. McIlorumV. MancusoE. LamprouD. DonnellyR. LarrañetaE. Development of a biodegradable subcutaneous implant for prolonged drug delivery using 3D printing.Pharmaceutics202012210510.3390/pharmaceutics1202010532013052
    [Google Scholar]
  165. JamrózW. SzafraniecJ. KurekM. JachowiczR. 3D printing in pharmaceutical and medical applications – Recent achievements and challenges.Pharm. Res.201835917610.1007/s11095‑018‑2454‑x29998405
    [Google Scholar]
  166. VazV.M. KumarL. 3D printing as a promising tool in personalized medicine.AAPS PharmSciTech20212214910.1208/s12249‑020‑01905‑833458797
    [Google Scholar]
  167. LiangY. DuanL. LuJ. XiaJ. Engineering exosomes for targeted drug delivery.Theranostics20211173183319510.7150/thno.5257033537081
    [Google Scholar]
  168. OrtegaA. Martinez-ArroyoO. FornerM.J. CortesR. Exosomes as drug delivery systems: Endogenous nanovehicles for treatment of systemic lupus erythematosus.Pharmaceutics2020131310.3390/pharmaceutics1301000333374908
    [Google Scholar]
  169. AbouM.B. SunL. WeiH. Approaches to optimizing dantrolene neuroprotection for the treatment of Alzheimer’s disease.Curr. Alzheimer Res.202017432432810.2174/156720501766620052220472232442084
    [Google Scholar]
  170. Lavanya JakkiS. SenthilV. ChandrasekarM. The blood brain barrier and its role in Alzheimer’s therapy: An overview.Curr. Drug Targets201718
    [Google Scholar]
  171. ZhuS. BaiQ. LiL. XuT. Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents.Comput. Struct. Biotechnol. J.2022202839284710.1016/j.csbj.2022.05.05735765655
    [Google Scholar]
  172. CunhaS. ForbesB. Sousa LoboJ.M. SilvaA.C. Improving drug delivery for Alzheimer’s disease through nose-to-brain delivery using nanoemulsions, nanostructured lipid carriers (NLC) and in situ hydrogels.Int. J. Nanomedicine2021164373439010.2147/IJN.S30585134234432
    [Google Scholar]
  173. PaulD. SanapG. ShenoyS. KalyaneD. KaliaK. TekadeR.K. Artificial intelligence in drug discovery and development.Drug Discov. Today2021261809310.1016/j.drudis.2020.10.01033099022
    [Google Scholar]
  174. PrashansaA. Artificial intelligence in drug discovery and development.J. Pharm. Vigil.20180621000e17310.4172/2329‑6887.1000e173
    [Google Scholar]
  175. WarrenJ.B. Translating the dose response into risk and benefit.Br. J. Clin. Pharmacol.201985102187219310.1111/bcp.1394930945324
    [Google Scholar]
  176. McGheeD.J.M. RitchieC.W. ZajicekJ.P. CounsellC.E. A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer’s disease and Parkinson’s disease.BMC Neurol.20161619210.1186/s12883‑016‑0606‑327312378
    [Google Scholar]
  177. ArnoldS.E. BetenskyR.A. Multicrossover randomized controlled trial designs in Alzheimer disease.Ann. Neurol.201884216817510.1002/ana.2528030014506
    [Google Scholar]
  178. OttenhoffL. VijverbergE.G.B. VisserL.N.C. VerijpM. PrinsN.D. Van der FlierW.M. SikkesS.A.M. Experiences of and recommendations on clinical trial design in Alzheimer’s disease from the participant’s point of view: A mixed-methods study in two clinical trial centers in the Netherlands.Alzheimers Res. Ther.20231517210.1186/s13195‑023‑01190‑037016435
    [Google Scholar]
  179. Randomized controlled trials: Overview, benefits, and limitations.Available from: https://www.medicalnewstoday.com/articles/280574
  180. WhiteH. SabarwalS. de HoopT. Randomized controlled trials (RCTs): Methodological briefs-impact evaluation No. 7. 2014.
  181. ThallP.F. Adaptive enrichment designs in clinical trials.Annu. Rev. Stat. Appl.20218139341110.1146/annurev‑statistics‑040720‑03281836212769
    [Google Scholar]
  182. CummingsJ. The role of biomarkers in Alzheimer's disease drug development.Adv. Exp. Med. Biol.20191118296110.1007/978‑3‑030‑05542‑4_2
    [Google Scholar]
  183. CareyA. FossatiS. Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer’s disease and dementia: New evidence, potential therapeutic strategies, and biomarkers.Alzheimers Dement.202319267169510.1002/alz.1287136401868
    [Google Scholar]
  184. SicaD.A. WeberM. The losartan intervention for endpoint reduction (LIFE) trial-have angiotensin-receptor blockers come of age?J. Clin. Hypertens.20024430130510.1111/j.1524‑6175.2002.01099.x12147937
    [Google Scholar]
  185. HaritonE. LocascioJ.J. Randomised controlled trials – The gold standard for effectiveness research.BJOG201812513171610.1111/1471‑0528.1519929916205
    [Google Scholar]
  186. SimonN. SimonR. Adaptive enrichment designs for clinical trials.Biostatistics201314461362510.1093/biostatistics/kxt01023525452
    [Google Scholar]
  187. CummingsJ. ApostolovaL. RabinoviciG.D. AtriA. AisenP. GreenbergS. HendrixS. SelkoeD. WeinerM. PetersenR.C. SallowayS. Lecanemab: Appropriate use recommendations.J. Prev. Alzheimers Dis.202310336237737357276
    [Google Scholar]
  188. BarcikowskaM. Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease.Lekarz POZ.201845370374
    [Google Scholar]
  189. AkramM. NawazA. Effects of medicinal plants on Alzheimer’s disease and memory deficits.Neural Regen. Res.201712466067010.4103/1673‑5374.20510828553349
    [Google Scholar]
  190. Guidance for industry and investigators safety reporting requirements for INDs and BA/BE StudiesUS Food and Drug Administration2012
    [Google Scholar]
  191. Guideline on good pharmacovigilance practices (GVP) - Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products.2017Available from: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vi-collection-management-and-submission-reports-suspected-adverse-reactions-medicinal-products-rev-2_en.pdf
  192. SinghR.K. Recent trends in the management of Alzheimer’s disease: Current therapeutic options and drug repurposing approaches.Curr. Neuropharmacol.202018986888210.2174/1570159X1866620012812192031989900
    [Google Scholar]
  193. NiuJ. StraubingerR.M. MagerD.E. Pharmacodynamic drug–drug interactions.Clin. Pharmacol. Ther.201910561395140610.1002/cpt.143430912119
    [Google Scholar]
  194. MaqboolM. DarM.A. RasoolS. BhatA.U. GeerM.I. Drug safety and Pharmacovigilance: An overview.J. Drug Deliv. Ther.201992-s54354810.22270/jddt.v9i2‑s.2469
    [Google Scholar]
  195. LavanA.H. GallagherP. Predicting risk of adverse drug reactions in older adults.Ther. Adv. Drug Saf.201671112210.1177/204209861561547226834959
    [Google Scholar]
  196. IvulichS. SnellG. Long-term management of elderly patients taking immunosuppressive medications.Aust. J. Gen. Pract.202049310010610.31128/AJGP‑10‑19‑513732113211
    [Google Scholar]
  197. HowardR. ZubkoO. BradleyR. HarperE. PankL. O’BrienJ. FoxC. TabetN. LivingstonG. BenthamP. McShaneR. BurnsA. RitchieC. ReevesS. LovestoneS. BallardC. NobleW. NilforooshanR. WilcockG. GrayR. Minocycline in Alzheimer Disease Efficacy (MADE) Trialist Group Minocycline at 2 different dosages vs. placebo for patients with mild Alzheimer disease.JAMA Neurol.202077216417410.1001/jamaneurol.2019.376231738372
    [Google Scholar]
  198. CummingsJ. MorstorfT. LeeG. Alzheimer’s drug-development pipeline: 2016.Alzheimers Dement.20162422223210.1016/j.trci.2016.07.00129067309
    [Google Scholar]
  199. MongeA.N. SigelmanD.W. TempleR.J. ChahalH.S. Use of US Food and Drug Administration expedited drug development and review programs by orphan and nonorphan novel drugs approved from 2008 to 2021.JAMA Network Open.2022511e223933630041014
    [Google Scholar]
  200. SalminenW.F. WilesM.E. StevensR.E. KesselheimA.S. Streamlining nonclinical drug development using the FDA 505(b)(2) new drug application regulatory pathway.Drug Discov. Today2019241465630041014
    [Google Scholar]
  201. HwangT.J. RossJ.S. VokingerK.N. KesselheimA.S. Association between FDA and EMA expedited approval programs and therapeutic value of new medicines: Retrospective cohort study.BMJ2020371.
    [Google Scholar]
  202. HanaiziZ. KwederS. ThorS. RibeiroS. MarcalA. Considering global development? Insights from applications for fda breakthrough therapy and EMA PRIME designations.Ther. Innov. Regul. Sci.202357232132810.1007/s43441‑022‑00475‑036307671
    [Google Scholar]
  203. CummingsJ. LeeG. NahedP. KambarM.E.Z.N. ZhongK. FonsecaJ. TaghvaK. Alzheimer’s disease drug development pipeline: 2022.Alzheimers Dement.202281e1229510.1002/trc2.1229535516416
    [Google Scholar]
  204. NauckM.A. QuastD.R. WefersJ. MeierJ.J. GLP-1 receptor agonists in the treatment of type 2 diabetes – State-of-the-art.Mol. Metab.20214610110210.1016/j.molmet.2020.10110233068776
    [Google Scholar]
  205. HsiehK.L. Plascencia-VillaG. LinK.H. PerryG. JiangX. KimY. Synthesize heterogeneous biological knowledge via representation learning for Alzheimer’s disease drug repurposing.iScience202326110567810.1016/j.isci.2022.10567836594024
    [Google Scholar]
  206. ShahS. FamtaP. FernandesV. BagasariyaD. CharankumarK. Kumar KhatriD. Bala SinghS. SrivastavaS. Quality by design steered development of Niclosamide loaded liposomal thermogel for Melanoma: In vitro and ex vivo evaluation.Eur. J. Pharm. Biopharm.202218011913610.1016/j.ejpb.2022.09.02436198344
    [Google Scholar]
  207. WuQ. SuS. CaiC. XuL. FanX. KeH. DaiZ. FangS. ZhuoY. WangQ. PanH. GuY. FangJ. Network Proximity-based computational pipeline identifies drug candidates for different pathological stages of Alzheimer’s disease.Comput. Struct. Biotechnol. J.2023211907192010.1016/j.csbj.2023.02.04136936813
    [Google Scholar]
  208. MadugulaS.S. JohnL. NagamaniS. GaurA.S. PoroikovV.V. SastryG.N. Molecular descriptor analysis of approved drugs using unsupervised learning for drug repurposing.Comput. Biol. Med.202113810485610.1016/j.compbiomed.2021.10485634555571
    [Google Scholar]
  209. GrabowskaM.E. HuangA. WenZ. LiB. WeiW.Q. Drug repurposing for Alzheimer’s disease from 2012–2022—a 10-year literature review.Front. Pharmacol.202314125770010.3389/fphar.2023.125770037745051
    [Google Scholar]
  210. FemminellaG.D. FrangouE. LoveS.B. BuszaG. HolmesC. RitchieC. LawrenceR. McFarlaneB. TadrosG. RidhaB.H. BannisterC. WalkerZ. ArcherH. CoulthardE. UnderwoodB.R. PrasannaA. KorantengP. KarimS. JunaidK. McGuinnessB. NilforooshanR. MacharouthuA. DonaldsonA. ThackerS. RussellG. MalikN. MateV. KnightL. KshemendranS. HarrisonJ. BrooksD.J. PassmoreA.P. BallardC. EdisonP. EdisonP. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: Study protocol for a randomised controlled trial (ELAD study).Trials201920119110.1186/s13063‑019‑3259‑x30944040
    [Google Scholar]
  211. PrinceM. WimoA. GurchetM. AliG. YuY. PrimeM. World Alzheimer Report 2015—the global impact of dementia: An analysis of prevalence, incidence, cost and trends.2015Available from: https://www.google.com/search?sca_esv=563294644&sxsrf=AB5stBh5CPoG8nZNHCtR-VCMOOEoBeo6SQ:1694062133183&q=Prince+M,+Wimo+A,+Gurchet+M,+Ali+G,+Yu+Y,+Prime+M.+World+Alzheimer+Report+2015—the+global+impact+of+dementia:+an+analysis+of+prevalence,+incidence,+cost+and+trends.+2015&spell=1&sa=X&ved=2ahUKEwj_ubOd2ZeBAxUxSWwGHbXjCBIQBSgAegQIChAB&biw=1536&bih=739&dpr=1.25
  212. WimoA. SeeherK. CataldiR. CyhlarovaE. DielemannJ.L. FrisellO. GuerchetM. JönssonL. MalahaA.K. NicholsE. PedrozaP. PrinceM. KnappM. DuaT. The worldwide costs of dementia in 2019.Alzheimers Dement.20231972865287310.1002/alz.1290136617519
    [Google Scholar]
  213. Levetiracetam: The anti-convulsant of choice for elderly patients with dementia.Available from: https://classic.clinicaltrials.gov/ct2/show/NCT01318408?id=NCT01318408&draw=2&rank=1&load=cart
  214. VosselK. RanasingheK.G. BeagleA.J. LaA. Ah PookK. CastroM. MizuiriD. HonmaS.M. VenkateswaranN. KoestlerM. ZhangW. MuckeL. HowellM.J. PossinK.L. KramerJ.H. BoxerA.L. MillerB.L. NagarajanS.S. KirschH.E. Effect of levetiracetam on cognition in patients with Alzheimer disease with and without epileptiform activity.JAMA Neurol.202178111345135410.1001/jamaneurol.2021.331034570177
    [Google Scholar]
  215. Sanford-Burnham researchers develop new drug that reverses loss of brain connections in Alzheimer’s.Available from: https://www.fiercebiotech.com/research/sanford-burnham-researchers-develop-new-drug-reverses-loss-of-brain-connections-alzheimer
  216. KabirM.T. SufianM.A. UddinM.S. BegumM.M. AkhterS. IslamA. MathewB. IslamM.S. AmranM.S. Md AshrafG. NMDA receptor antagonists: Repositioning of memantine as a multitargeting agent for Alzheimer’s therapy.Curr. Pharm. Des.201925333506351810.2174/138161282566619101110244431604413
    [Google Scholar]
  217. KaeberleinM. GalvanV. Rapamycin and Alzheimer’s disease: Time for a clinical trial?Sci. Transl. Med.201911476eaar428910.1126/scitranslmed.aar428930674654
    [Google Scholar]
  218. CarosiJ.M. SargeantT.J. Rapamycin and Alzheimer disease: A double-edged sword?Autophagy20191581460146210.1080/15548627.2019.161582331066320
    [Google Scholar]
  219. GhiamM.K. PatelS.D. HofferA. SelmanW.R. HofferB.J. HofferM.E. Drug repurposing in the treatment of traumatic brain injury.Front. Neurosci.20211563548310.3389/fnins.2021.63548333833663
    [Google Scholar]
  220. WongC. GregoryJ.M. LiaoJ. EganK. VesterinenH.M. Ahmad KhanA. AnwarM. BeaganC. BrownF.S. CafferkeyJ. CardinaliA. ChiamJ.Y. ChiangC. CollinsV. DormidoJ. ElliottE. FoleyP. FooY.C. Fulton-HumbleL. GaneA.B. GlasmacherS.A. HeffernanÁ. JayaprakashK. JayasuriyaN. KaddouriA. KiernanJ. LanglandsG. LeightonD. LiuJ. LyonJ. MehtaA.R. MengA. NguyenV. ParkN.H. QuigleyS. RashidY. SalzingerA. ShiellB. SinghA. SoaneT. ThompsonA. TomalaO. WaldronF.M. SelvarajB.T. ChatawayJ. SwinglerR. ConnickP. PalS. ChandranS. MacleodM. Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.BMJ Open2023132e06416910.1136/bmjopen‑2022‑06416936725099
    [Google Scholar]
  221. DesaiR.J. VarmaV.R. GerhardT. SegalJ. MahesriM. ChinK. NonnenmacherE. GabbetaA. MammenA.M. VarmaS. HortonD.B. KimS.C. SchneeweissS. ThambisettyM. Targeting abnormal metabolism in Alzheimer’s disease: The drug repurposing for effective Alzheimer’s medicines (dream) study.Alzheimers Dement.202061e1209510.1002/trc2.1209533304987
    [Google Scholar]
  222. EhrhardtS. PorsteinssonA.P. MunroC.A. RosenbergP.B. PollockB.G. DevanandD.P. MintzerJ. RajjiT.K. IsmailZ. SchneiderL.S. BakshS.N. DryeL.T. AvramopoulosD. ShadeD.M. LyketsosC.G. S-CitAD Research Group Escitalopram for agitation in Alzheimer’s disease (S-CitAD): Methods and design of an investigator-initiated, randomized, controlled, multicenter clinical trial.Alzheimers Dement.201915111427143610.1016/j.jalz.2019.06.494631587995
    [Google Scholar]
  223. FaroukI.A. LowZ.Y. PuniyamurtiA. ZabidiN.Z. AminM.K.A. LalS.K. Genomic approaches for drug repositioning.Biomedical Translational ResearchSpringerSingapore20224972
    [Google Scholar]
  224. CookM.A. WrightG.D. The past, present, and future of antibiotics.Sci. Transl. Med.202214657eabo779310.1126/scitranslmed.abo779335947678
    [Google Scholar]
  225. WangR. ReddyP.H. Role of glutamate and NMDA receptors in Alzheimer’s disease.J. Alzheimers Dis.20175741041104810.3233/JAD‑16076327662322
    [Google Scholar]
  226. SheldonA.L. RobinsonM.B. The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention.Neurochem. Int.2007516-733335510.1016/j.neuint.2007.03.01217517448
    [Google Scholar]
  227. MeyerT. MünchC. VölkelH. BoomsP. LudolphA.C. The EAAT2 (GLT-1) gene in motor neuron disease: Absence of mutations in amyotrophic lateral sclerosis and a point mutation in patients with hereditary spastic paraplegia.J. Neurol. Neurosurg. Psychiatry199865459459610.1136/jnnp.65.4.5949771796
    [Google Scholar]
  228. JacksonM. SteersG. Nigel LeighP. MorrisonK.E. Polymorphisms in the glutamate transporter gene EAAT2 in European ALS patients.J. Neurol.1999246121140114410.1007/s00415005053210653305
    [Google Scholar]
  229. RosenblumL.T. TrottiD. EAAT2 and the molecular signature of amyotrophic lateral sclerosis.Adv. Neurobiol.20171611713610.1007/978‑3‑319‑55769‑4_628828608
    [Google Scholar]
  230. AmbatiJ. NeuronB.F. Mechanisms of age-related macular degeneration.Neuron2012751263910.1016/j.neuron.2012.06.018
    [Google Scholar]
  231. RothsteinJ PatelS ReganM NatureCH. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression.Nature20054337021737710.1038/nature03180
    [Google Scholar]
  232. ObrenovichM. JaworskiH. TadimallaT. MistryA. SykesL. PerryG. BonomoR. The role of the microbiota–gut–brain axis and antibiotics in ALS and neurodegenerative diseases.Microorganisms20208578410.3390/microorganisms805078432456229
    [Google Scholar]
  233. Clinical trial ceftriaxone in subjects With ALS - Full text view.Available from: https://clinicaltrials.gov/ct2/show/NCT00349622
  234. CudkowiczM. TitusS. KearneyM. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: A multi-stage, randomised, double-blind, placebo-controlled trial.Lancet Neurol.201413111083109110.1016/S1474‑4422(14)70222‑4
    [Google Scholar]
  235. McDonnellE. SchoenfeldD. PaganoniS. AtassiN. Causal inference methods to study gastric tube use in amyotrophic lateral sclerosis.Neurology201789141483148910.1212/WNL.000000000000453428864675
    [Google Scholar]
  236. YimerE.M. HisheH.Z. TuemK.B. Repurposing of the β-lactam antibiotic, ceftriaxone for neurological disorders: A review.Front. Neurosci.20191323610.3389/fnins.2019.0023630971875
    [Google Scholar]
  237. MittalS. BjørnevikK. ImD.S. FlierlA. DongX. LocascioJ.J. AboK.M. LongE. JinM. XuB. XiangY.K. RochetJ.C. EngelandA. RizzuP. HeutinkP. BartelsT. SelkoeD.J. CaldaroneB.J. GlicksmanM.A. KhuranaV. SchüleB. ParkD.S. RiiseT. ScherzerC.R. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease.Science2017357635489189810.1126/science.aaf393428860381
    [Google Scholar]
  238. StefanisL. α-Synuclein in Parkinson’s disease.Cold Spring Harb. Perspect. Med.201222a00939910.1101/cshperspect.a00939922355802
    [Google Scholar]
  239. NtetsikaT. PapathomaP.E. MarkakiI. Novel targeted therapies for Parkinson’s disease.Mol. Med.20212711710.1186/s10020‑021‑00279‑233632120
    [Google Scholar]
  240. ItohN. OhtaH. Roles of FGF20 in dopaminergic neurons and Parkinson’s disease.Front. Mol. Neurosci.20136MAY1510.3389/fnmol.2013.0001523754977
    [Google Scholar]
  241. LiuY. DengJ. LiuY. LiW. NieX. FGF, mechanism of action, role in Parkinson’s disease, and therapeutics.Front. Pharmacol.20211267572510.3389/fphar.2021.67572534234672
    [Google Scholar]
  242. ZhengH. FridkinM. YoudimM. New approaches to treating Alzheimer’s disease.Perspect. Medicin. Chem.20157PMC.S1321010.4137/PMC.S1321025733799
    [Google Scholar]
  243. FletcherE.J.R. JamiesonA.D. WilliamsG. DohertyP. DutyS. Targeted repositioning identifies drugs that increase fibroblast growth factor 20 production and protect against 6-hydroxydopamine-induced nigral cell loss in rats.Sci. Rep.201991833610.1038/s41598‑019‑44803‑131171821
    [Google Scholar]
  244. ParkK. Risk of stroke associated with nonsteroidal anti-inflammatory drugs.Vasc. Health Risk Manag.201410253210.2147/VHRM.S54159
    [Google Scholar]
  245. NeuroprotectiveK NatarajanK YuJ HansonCK. Neuroprotective effects and therapeutic potential of the citrus flavonoid hesperetin in neurodegenerative diseases.Nutrients20221411222810.3390/nu14112228
    [Google Scholar]
  246. MarkulinI. MatasinM. TurkV.E. Salković-PetrisicM. Challenges of repurposing tetracyclines for the treatment of Alzheimer’s and Parkinson’s disease.J. Neural Transm.20221295-677380410.1007/s00702‑021‑02457‑234982206
    [Google Scholar]
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